Adenosine protects cardiomyocytes against acrolein-induced cardiotoxicity by enhancing mitochondrial homeostasis, antioxidant defense, and autophagic flux via ERK-activated FoxO1 upregulation.

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5'-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.

Efficacy, safety, and cost-effectiveness of pegylated PEG-rhg-CSF in pediatric patients receiving high-intensity chemotherapy: results from a phase II study.

Background: High-intensity chemotherapy can cause life-threatening complications in pediatric patients. Therefore, this study investigated safety and efficacy of long-acting pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF; Jinyouli®) in children undergoing high-intensity chemotherapy. Methods: Treatment-naive patients received post-chemotherapy PEG-rhG-CSF as primary prophylaxis for two cycles. The primary endpoints were drug-related adverse events (AEs) and bone pain scores. Secondary endpoints included grade 3-4 neutropenia, duration of neutropenia recovery, absolute neutrophil count changes, febrile neutropenia (FN), reduced chemotherapy intensity, antibiotic usage, and AE severity. The cost-effectiveness of PEG-rhG-CSF was compared with that of rhG-CSF (Ruibai®). Results: Here, 307 and 288 patients underwent one and two PEG-rhG-CSF cycles, respectively. Ninety-one patients experienced drug-related AEs, primarily bone pain (12.7%). Moreover, Grade 3-4 neutropenia and FN were observed. Median FN durations were 3.0 days in both cycles. No drug-related delays were observed during chemotherapy. One patient experienced grade 4 neutropenia-induced reduction in chemotherapy intensity during cycle 2. In total, 138 patients received antibiotics. PEG-rhG-CSF exhibited superior cost-effectiveness compared to rhG-CSF. Conclusion: Our findings indicate that PEG-rhG-CSF is safe, efficient, and cost-effective in pediatric patients undergoing high-intensity chemotherapy, providing preliminary evidence warranting further randomized controlled trials.

Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis.

OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

A crisis in clinical research.

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.

Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. METHODS: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. RESULTS: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. CONCLUSION: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

Bayesian sequential monitoring strategies for trials of digestive cancer therapeutics.

BACKGROUND: New therapeutics in oncology have presented challenges to existing paradigms and trial designs in all phases of drug development. As a motivating example, we considered an ongoing phase II trial planned to evaluate the combination of a MET inhibitor and an anti-PD-L1 immunotherapy to treat advanced oesogastric carcinoma. The objective of the paper was to exemplify the planning of an adaptive phase II trial with novel anti-cancer agents, including prolonged observation windows and joint sequential evaluation of efficacy and toxicity. METHODS: We considered various candidate designs and computed decision rules assuming correlations between efficacy and toxicity. Simulations were conducted to evaluate the operating characteristics of all designs. RESULTS: Design approaches allowing continuous accrual, such as the time-to-event Bayesian Optimal Phase II design (TOP), showed good operating characteristics while ensuring a reduced trial duration. All designs were sensitive to the specification of the correlation between efficacy and toxicity during planning, but TOP can take that correlation into account more easily. CONCLUSIONS: While specifying design working hypotheses requires caution, Bayesian approaches such as the TOP design had desirable operating characteristics and allowed incorporating concomittant information, such as toxicity data from concomitant observations in another relevant patient population (e.g., defined by mutational status).

A randomized phase II trial of Captem or Folfiri as second-line therapy in neuroendocrine carcinomas.

BACKGROUND: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients. METHODS: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers. RESULTS: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS. CONCLUSION: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum. GOV IDENTIFIER: NCT03387592.

Effect and Safety of Apatinib as Neoadjuvant Therapy in Locally Advanced Differentiated Thyroid Cancer: A Phase 2 Trial.

Context: Presently, there is a paucity of prospective clinical trials investigating neoadjuvant therapy for locally advanced thyroid cancer. Objective: This study was a multicenter, open-label, single-arm, phase II trial evaluating the efficacy and safety of apatinib as neoadjuvant therapy in patients with local advanced differentiated thyroid cancer (DTC). Methods: Patients were treated with preoperative apatinib over a course of 2 to 4 cycles, culminating in surgical resection. The primary endpoints were objective response rate (ORR) and disease control rate (DCR); the secondary endpoints were the rate of R0 surgery, alterations in serum thyroglobulin levels, disease-free survival, and adverse events (AEs). Results: A total of 14 patients who met the inclusion criteria were administered neoadjuvant apatinib. Among these, 13 patients underwent surgical procedures following apatinib treatment and were enrolled in the ITT population. The ORR was 53.8% and the DCR was 100%. Of the patients, 84.6% received R0 surgery, while the remaining 15.4% underwent R1 resection. Predominant among the observed AEs were hypertension, hand-foot syndrome, hepatic dysfunction, proteinuria, and hypothyroidism, with no instances of grade 4 or 5 AEs reported. Subsequent to surgery, patients were followed up for a median period of 34 months, during which disease progression occurred in 5 individuals (35.7%), encompassing 3 cases of locoregional recurrences and 2 cases of distant metastases. Conclusion: Apatinib may be an effective agent in the use of neoadjuvant therapy for locally advanced DTC. Patients may therefore benefit from surgical outcomes and their long-term prognosis.

Developing targeted therapeutics for hepatocellular carcinoma: a critical assessment of promising phase II agents.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the first for primary liver tumors. In recent years greater therapeutic advancement was represented by employment of tyrosine kinase inhibitors (TKIs) either in monotherapy or in combination with immune checkpoint inhibitors (ICIs). AREAS COVERED: Major attention was given to target therapies in the last couple of years, especially in those currently under phase II trials. Priority was given either to combinations of novel ICI and TKIs or those targeting alternative mutations of major carcinogenic pathways. EXPERT OPINION: As TKIs are playing a more crucial role in HCC therapeutic strategies, it is fundamental to further expand molecular testing and monitoring of acquired resistances. Despite the recent advancement in both laboratory and clinical studies, further research is necessary to face the discrepancy in clinical practice.

Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF).

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Hypofractionated proton and carbon ion beam radiotherapy for sacrococcygeal chordoma (ISAC): An open label, randomized, stratified, phase II trial.

INTRODUCTION: Sacrococcygeal chordomas have high recurrence rates and are challenging to treat. METHODS: In this phase II prospective, randomized, stratified trial, the safety and feasibility of hypofractionated ion radiation therapy were investigated. The primary focus was monitored through the incidence of Grade 3-5 NCI-CTC-AE toxicity. Secondary endpoints included local progression-free (LPFS) and overall survival (OS). RESULTS: The study enrolled 82 patients with primary (87 %) and recurrent (13 %) inoperable or incompletely resected sacral chordomas from January 2013 to July 2022, divided equally into proton therapy (Arm A) and carbon ion beam therapy (Arm B) groups, each receiving a total dose of 64 Gy (RBE) in 16 fractions, 5-6 fractions per week. Overall 74 % of patients received no previous surgery and 66 % of tumors were confirmed by a brachyury staining. The mean and median Gross Tumor Volume at the time of treatment (GTV) was 407 ml and 185 ml, respectively. The median follow-up of the surviving patients was 44.7 months, and the 2-year and 4-year OS rates were 96 % and 81 %, respectively. Factors such as smaller GTV and younger age trended towards better OS. The LPFS after 2-year and 4-year was 84 % and 70 %, respectively. Male gender emerged as a significant predictor of LPFS. There was no significant difference between the treatment groups. We observed five grade 4 wound healing disorders (6 %). CONCLUSION: The initial response rates were promising; however local control was not sustained. More comparative research on fractionation schemes is essential to refine treatment approaches for inoperable sacral chordoma.

How to Balance Prognostic Factors in Controlled Phase II Trials: Stratified Permuted Block Randomization or Minimization? An Analysis of Clinical Trials in Digestive Oncology.

In controlled phase II trials, major prognostic factors need to be well balanced between arms. The main procedures used are SPBR (Stratified Permuted Block Randomization) and minimization. First, we provide a systematic review of the treatment allocation procedure used in gastrointestinal oncology controlled phase II trials published in 2019. Second, we performed simulations using data from six phase II studies to measure the impacts of imbalances and bias on the efficacy estimations. From the 40 articles analyzed, all mentioned randomization in both the title and abstract, the median number of patients included was 109, and 77.5% were multicenter. Of the 27 studies that reported at least one stratification variable, 10 included the center as a stratification variable, 10 used minimization, 9 used SBR, and 8 were unspecified. In real data studies, the imbalance increased with the number of centers. The total and marginal imbalances were higher with SBR than with minimization, and the difference increased with the number of centers. The efficiency estimates per arm were close to the original trial estimate in both procedures. Minimization is often used in cases of numerous centers and guarantees better similarity between arms for stratification variables for total and marginal imbalances in phase II trials.

Efficacy and safety of pentosan polysulfate sodium in people with symptomatic knee osteoarthritis and dyslipidaemia: protocol of the MaRVeL trial.

INTRODUCTION: Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia. METHODS AND ANALYSIS: MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Transgender people in clinical trials of drugs and biologics: An analysis of ClinicalTrials.gov from 2007 to 2023.

AIMS: Transgender people have unmet health needs related to chronic conditions such as dementia, osteoporosis and hypertension. Community-driven advocacy increased transgender representation in phase III trials for pharmacological prevention of HIV, but the extent to which drug trials for other conditions have included transgender people is unknown. We investigated the extent to which trials of drugs and biologics represented transgender people across therapeutic areas on ClinicalTrials.gov. METHODS: Cross-sectional analysis of trials of drugs and biologics registered on ClinicalTrials.gov from 2007-2023. We included efficacy and effectiveness trials (phase II-IV) with transgender-related terms (e.g. 'transgend*'). We labelled trials as Inclusive or Exclusive of transgender people using the trial eligibility criteria. We compared trials (therapeutic area, trial design, enrolment), summarized trials registered from 2008 onward and characterized participant enrolment for Inclusive trials with primary trial publications. We summarized continuous data using median (range), categorical data using frequencies and percentages and compared trial characteristics using Fisher's exact test. RESULTS: Ninety-seven trials represented transgender people. Characteristics were similar between 85 Inclusive and 12 Exclusive trials. Among Inclusive trials, 58% focused on infectious diseases (e.g. treatment or prevention of HIV and COVID-19), 15% on mental health (e.g. post-traumatic stress disorder, substance use-related disorders), and the remainder focused on endocrine (9%), pain (5%), digestive system disorders (1%) and neoplasms (1%). Twenty (of 25) trials reported enrolment of transgender participants in primary trial publications or reported results. CONCLUSION: Transgender-inclusive trials have increased since 2008. Most trials focused on infectious diseases and mental health. Investigators should increase opportunities to include of transgender people in trials of drugs and biologics for chronic diseases.

Acute adverse events of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for early breast cancer in Japan: an interim analysis of the multi-institutional phase II UPBEAT study.

BACKGROUND: The applicability of ultra-hypofractionated (ultra-HF) whole-breast irradiation (WBI) remains unknown in Japanese women. This study aimed to evaluate the safety and efficacy of this approach among Japanese women and report the results of an interim analysis performed to assess acute adverse events (AEs) and determine whether it was safe to continue this study. METHODS: We enrolled Japanese women with invasive breast cancer or ductal carcinoma in situ who had undergone breast-conserving surgery, were aged ≥ 40 years, had pathological stages of Tis-T3 N0-N1, and had negative surgical margins. Ultra-HF-WBI was delivered at 26 Gy in five fractions over one week. When the number of enrolled patients reached 28, patient registration was paused for three months. The endpoint of the interim analysis was the proportion of acute AEs of grade ≥ 2 (Common Terminology Criteria for Adverse Events v5.0) within three months. RESULTS: Of the 28 patients enrolled from seven institutes, 26 received ultra-HF-WBI, and 2 were excluded due to postoperative infections. No AEs of grade ≥ 3 occurred. One patient (4%) experienced grade 2 radiation dermatitis, and 18 (69%) had grade 1 radiation dermatitis. The other acute grade 1 AEs experienced were skin hyperpigmentation (n = 10, 38%); breast pain (n = 4, 15%); superficial soft tissue fibrosis (n = 3, 12%); and fatigue (n = 1, 4%). No other acute AEs of grade ≥ 2 were detected. CONCLUSIONS: Acute AEs following ultra-HF-WBI were within acceptable limits among Japanese women, indicating that the continuation of the study was appropriate.

Event-free survival in relapsed and refractory rhabdomyosarcoma treated on cooperative group phase II trials: A report from the Children's Oncology Group.

BACKGROUND: Novel therapies are needed for relapsed and refractory rhabdomyosarcoma (RRMS). Phase II clinical trials in RRMS have typically utilized radiologic response as the primary activity endpoint, an approach that poses several limitations in RRMS. In this analysis, we aimed to estimate an event-free survival (EFS) endpoint for RRMS that could be used as a benchmark for future studies. PROCEDURE: We performed a retrospective study of patients with RRMS enrolling on 13 single-agent phase II Children's Oncology Group and legacy group trials from 1997 to 2016. All included trials used radiographic response as their primary activity endpoint. Six-month EFS was estimated from time of trial enrollment with 95% confidence intervals. Clinical characteristics, including trial of enrollment, sex, age, race, histology, number of prior chemotherapies, and radiographic response were evaluated for their impact on 6-month EFS. RESULTS: We identified 175 patients across 13 trials. The 6-month EFS was 16.8% (11.6%-22.8%). No differences were seen in 6-month EFS based on age, sex, race, or histology. There were nonsignificant trends toward improved 6-month EFS for patients with less than or equal to two prior lines of therapy versus higher than two, for patients enrolled on trials that achieved their primary radiographic response endpoint versus trials that did not, and for patients who achieved complete or partial response compared to those achieving stable disease. CONCLUSIONS: The prognosis of RRMS enrolled on single-agent phase II trials is poor. This pooled 6-month EFS of RRMS on single-agent trials may be used as a RRMS-specific benchmark for future single-agent phase II trials.

ADME Gene-Related Pharmacogenomic Labeling of FDA-Approved Drugs: Comparison with Clinical Pharmacogenetics Implementation Consortium (CPIC) Evidence Levels.

Pharmacogenomics (PGx) can facilitate the transition to patient-specific drug regimens and thus improve their efficacy and reduce toxicity. The aim of this study was to evaluate the overlap of PGx classification for drug absorption, distribution, metabolism, and elimination (ADME)-related genes in the U.S. Food and Drug Administration (FDA) PGx labeling and in the Clinical Pharmacogenetics Implementation Consortium (CPIC) database. FDA-approved drugs and PGx labeling for ADME genes were identified in the CPIC database. Drugs were filtered by their association with ADME (pharmacokinetics)-related genes, PGx FDA labeling class, and CPIC evidence level. FDA PGx labeling was classified as either actionable, informative, testing recommended, or testing required, and varying CPIC evidence levels as either A, B, C, or D. From a total of 442 ADME and non-ADME gene-drug pairs in the CPIC database, 273, 55, and 48 pairs were excluded for lack of FDA labeling, mixed CPIC evidence level provisional classification, and non-ADME gene-drug pairs, respectively. The 66 ADME gene-drug pairs were classified into the following categories: 10 (15%) informative, 49 (74%) actionable, 6 (9%) testing recommended, and 1 (2%) testing required. CYP2D6 was the most prevalent gene among the FDA PGx labeling. From the ADME gene-drug pairs with both FDA and CPIC PGx classification, the majority of the drugs were for depression, cancer, and pain medications. The ADME gene-drug pairs with FDA PGx labeling considerably overlap with CPIC classification; however, a large number of ADME gene-drug pairs have only CPIC evidence levels but not FDA classification. PGx actionable labeling was the most common classification, with CYP2D6 as the most prevalent ADME gene in the FDA PGx labeling. Health professionals can impact therapeutic outcomes via pharmacogenetic interventions by analyzing and reconciling the FDA labels and CPIC database.

Definitive results of a prospective non-randomized phase 2 study on stereotactic body radiation therapy (sbrt) for medically inoperable lung and liver oligometastases from breast cancer.

BACKGROUND AND PURPOSE: To report mature results for local control and survival in oligometastatic (OM) breast cancer patients treated with stereotactic body radiotherapy (SBRT) on lung and/or liver lesions in a phase II trial. METHODS: This is a prospective non-randomized phase II trial (NCT02581670) which enrolled patients from 2015 to 2021. Eligibility criteria included: age > 18 years, ECOG 0-2, diagnosis of breast cancer, maximum of 4 lung/liver lesions (with a maximum diameter < 5 cm), metastatic disease confined to the lungs and liver or extrapulmonary or extrahepatic disease stable or responding to systemic therapy. The primary end-points were local control (LC) and treatment-related toxicities. The secondary end-points included overall survival (OS), distant metastasis-free survival (DMFS), time to next systemic therapy (TTNS), poly-progression free survival (PPFS). RESULTS: The study included 64 patients with a total of 90 lesions treated with SBRT. LC at 1 and 2 years was 94.9 %, 91 % at 3 years. Median local control was not reached. Median OS was 16.5 months, OS at 1, 2 and 3 years was 87.5 %, 60.9 % and 51.9 %, respectively. Median DMFS was 8.3 months, DMFS at 1, 2 and 3 years was 38.1 %, 20.6 % and 16 % respectively. At univariate analysis, local response to SBRT was found to be statistically linked with better OS, DMFS and STFS. CONCLUSION: SBRT is a safe and valid option in oligometastatic breast cancer patients, with very high rates of local control. An optimal selection of patients is likely needed to improve survival outcomes and reduce the rate of distant progression.