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Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.
Tricou, V, Yu, D, Reynales, H, Biswal, S, Saez-Llorens, X, Sirivichayakul, C, Lopez, P, Borja-Tabora, C, Bravo, L, Kosalaraksa, P, et al
The Lancet. Global health. 2024;(2):e257-e270
Abstract
BACKGROUND About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine TAK-003 in preventing symptomatic dengue disease of any severity and due to any dengue virus (DENV) serotypes in children and adolescents. METHODS In this ongoing double-blind, randomised, placebo-controlled trial, we enrolled healthy participants aged 4-16 years at 26 medical and research centres across eight dengue-endemic countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). The main exclusion criteria were febrile illness (body temperature ≥38°C) at the time of randomisation, hypersensitivity or allergy to any of the vaccine components, pregnancy or breastfeeding, serious chronic or progressive disease, impaired or altered immune function, and previous receipt of a dengue vaccine. Participants were randomly assigned 2:1 (stratified by age and region) using an interactive web response system and dynamic block assignment to receive two subcutaneous doses of TAK-003 or placebo 3 months apart. Investigators, participants, and their parents or legal guardians were blinded to group assignments. Active febrile illness surveillance and RT-PCR testing of febrile illness episodes were performed for identification of virologically confirmed dengue. Efficacy outcomes were assessed in the safety analysis set (all randomly assigned participants who received ≥1 dose) and the per protocol set (all participants who had no major protocol violations), and included cumulative vaccine efficacy from first vaccination to approximately 4·5 years after the second vaccination. Serious adverse events were monitored throughout. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS Between Sept 7, 2016, and March 31, 2017, 20 099 participants were randomly assigned (TAK-003, n=13 401; placebo, n=6698). 20 071 participants (10 142 [50·5%] males; 9929 [49·5%] females; safety set) received TAK-003 or placebo, with 18 257 (91·0%) completing approximately 4·5 years of follow-up after the second vaccination (TAK-003, 12 177/13 380; placebo, 6080/6687). Overall, 1007 (placebo: 560; TAK-003: 447) of 27 684 febrile illnesses reported were virologically confirmed dengue, with 188 cases (placebo: 142; TAK-003: 46) requiring hospitalisation. Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set). In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4. During part 3 of the trial (approximately 22-57 months after the first vaccination), serious adverse events were reported for 664 (5·0%) of 13 380 TAK-003 recipients and 396 (5·9%) of 6687 placebo recipients; 17 deaths (6 in the placebo group and 11 in the TAK-003 group) were reported, none were considered study-vaccine related. INTERPRETATION TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals. FUNDING Takeda Vaccines. TRANSLATIONS For the Portuguese, Spanish translations and plain language summary of the abstract see Supplementary Materials section.
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Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer.
Landry, CA, Blanter, J, Ru, M, Fasano, J, Klein, P, Shao, T, Bhardwaj, A, Tiersten, A
Oncology. 2024;(1):9-16
Abstract
INTRODUCTION The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2-) MBC and recurrent ovarian cancer (ROC). METHODS Cohorts of 3-6 patients with HER2- MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. PRIMARY ENDPOINT the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. RESULTS Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2- MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. CONCLUSION The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.
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Phase II Study of Eribulin plus Pembrolizumab in Metastatic Soft-tissue Sarcomas: Clinical Outcomes and Biological Correlates.
Haddox, CL, Nathenson, MJ, Mazzola, E, Lin, JR, Baginska, J, Nau, A, Weirather, JL, Choy, E, Marino-Enriquez, A, Morgan, JA, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024;(7):1281-1292
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PURPOSE Eribulin modulates the tumor-immune microenvironment via cGAS-STING signaling in preclinical models. This non-randomized phase II trial evaluated the combination of eribulin and pembrolizumab in patients with soft-tissue sarcomas (STS). PATIENTS AND METHODS Patients enrolled in one of three cohorts: leiomyosarcoma (LMS), liposarcomas (LPS), or other STS that may benefit from PD-1 inhibitors, including undifferentiated pleomorphic sarcoma (UPS). Eribulin was administered at 1.4 mg/m2 i.v. (days 1 and 8) with fixed-dose pembrolizumab 200 mg i.v. (day 1) of each 21-day cycle, until progression, unacceptable toxicity, or completion of 2 years of treatment. The primary endpoint was the 12-week progression-free survival rate (PFS-12) in each cohort. Secondary endpoints included the objective response rate, median PFS, safety profile, and overall survival (OS). Pretreatment and on-treatment blood specimens were evaluated in patients who achieved durable disease control (DDC) or progression within 12 weeks [early progression (EP)]. Multiplexed immunofluorescence was performed on archival LPS samples from patients with DDC or EP. RESULTS Fifty-seven patients enrolled (LMS, n = 19; LPS, n = 20; UPS/Other, n = 18). The PFS-12 was 36.8% (90% confidence interval: 22.5-60.4) for LMS, 69.6% (54.5-89.0) for LPS, and 52.6% (36.8-75.3) for UPS/Other cohorts. All 3 patients in the UPS/Other cohort with angiosarcoma achieved RECIST responses. Toxicity was manageable. Higher IFNα and IL4 serum levels were associated with clinical benefit. Immune aggregates expressing PD-1 and PD-L1 were observed in a patient that completed 2 years of treatment. CONCLUSIONS The combination of eribulin and pembrolizumab demonstrated promising activity in LPS and angiosarcoma.
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Impact of Weight Management on Obesity-Driven Biomarkers of Prostate Cancer Progression.
Bechtel, MD, Michel, C, Srinivasan, P, Chalise, P, Parker, WP, Mirza, M, Thrasher, B, Gibbs, HD, DiGiovanni, J, Hamilton-Reeves, J
The Journal of urology. 2024;(4):552-562
Abstract
PURPOSE Excess body and visceral fat increase the risk of death from prostate cancer (PCa). This phase II study aimed to test whether weight reduction by > 5% total body weight counteracts obesity-driven PCa biomarkers. MATERIALS AND METHODS Forty men scheduled for prostatectomy were randomized into intervention (n = 20) or control (n = 20) arms. Intervention participants followed a weight management program for 4 to 16 weeks before and 6 months after surgery. Control participants received standardized educational materials. All participants attended visits at baseline, 1 week before surgery, and 6 months after surgery. Circulating immune cells, cytokines, and chemokines were evaluated. Weight loss, body composition/distribution, quality of life, and nutrition literacy were assessed. Prostate tissue samples obtained from biopsy and surgery were analyzed. RESULTS From baseline to surgery (mean = 5 weeks), the intervention group achieved 5.5% of weight loss (95% CI, 4%-7%). Compared to the control, the intervention also reduced insulin, total cholesterol, LDL cholesterol, leptin, leptin:adiponectin ratio, and visceral adipose tissue. The intervention group had reduced c-peptide, plasminogen-activator-inhibitor-1, and T cell count from baseline to surgery. Myeloid-derived suppressor cells were not statistically different by group. Intervention group anthropometrics improved, including visceral and overall fat loss. No prostate tissue markers changed significantly. Quality of life measures of general and emotional health improved in the intervention group. The intervention group maintained or kept losing to a net loss of 11% initial body weight (95% CI, 8%-14%) at the study end. CONCLUSIONS Our study demonstrated improvements in body composition, PCa biomarkers, and quality of life with a weight management intervention.
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Effects of vitamin D levels during pregnancy on prematurity: a systematic review protocol.
Barbosa, O, Sim-Sim, M, Silvestre, MP, Pedro, C, Cruz, D
BMJ open. 2024;(2):e076702
Abstract
INTRODUCTION Prematurity is an urgent public health problem worldwide. Recent studies associate maternal hypovitaminosis D during pregnancy with an increased risk of prematurity. However, the evidence on this association remains inconclusive, and there is lack of consensus in the literature. The exact mechanism by which low vitamin D levels may increase the risk of preterm birth is not yet fully understood. Nevertheless, it is known that vitamin D may play a role in maintaining a healthy pregnancy by regulating inflammation and immunomodulation by acting on the maternal and fetal immune systems. Inflammation and immune dysregulation are both associated with preterm birth, and low vitamin D levels may exacerbate these processes. The results of this review may have important implications for clinical practice and public health policy, particularly regarding vitamin D supplementation during pregnancy. METHODS AND ANALYSIS A systematic review of the literature will be conducted. The search will be performed in electronic databases: CINAHL; MEDLINE; Cochrane Central Register of Controlled Trials; Cochrane Library; Academic Search Complete; Information Science and Technology Abstracts; MedicLatina; SCOPUS; PubMed; and Google Scholar, with the chronological range of January 2018 to November 2022. The search strategy will include the following Medical Subject Headings or similar terms: 'Vitamin D'; '25-hydroxyvitamin D'; 'Hypovitaminosis D'; 'Pregnancy'; 'Pregnant women'; 'Expectant mother'; 'Prematurity'; 'Premature birth'; 'Premature delivery'; 'Preterm birth'; and 'Preterm labour'. This review will include quantitative primary studies, both experimental (clinical trials) and observational (cohort, cross-sectional, and case-control). The quality of each selected study and the results obtained will be assessed by two reviewers separately, using the Cochrane risk of bias tool for evaluating randomised clinical trials or the Newcastle Ottawa Scale for non-randomised studies, following the respective checklist. In case of disagreement, a third reviewer will be consulted. ETHICS AND DISSEMINATION This study does not involve human subjects and therefore does not require ethics approval. The results will be disseminated through publication in a peer-reviewed scientific journal and through conference presentations. All changes made to the protocol will be registered in PROSPERO, with information on the nature and justification for the changes made. PROSPERO REGISTRATION NUMBER CRD42022303901.
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Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.
Wang, K, Xiang, YJ, Yu, HM, Cheng, YQ, Liu, ZH, Qin, YY, Shi, J, Guo, WX, Lu, CD, Zheng, YX, et al
Nature medicine. 2024;(3):708-715
Abstract
Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .
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A randomized first-in-human phase I trial of differentially adjuvanted Pfs48/45 malaria vaccines in Burkinabé adults.
Tiono, AB, Plieskatt, JL, Ouedraogo, A, Soulama, BI, Miura, K, Bougouma, EC, Naghizadeh, M, Barry, A, Yaro, JBB, Ezinmegnon, S, et al
The Journal of clinical investigation. 2024;(7)
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BACKGROUNDMalaria transmission-blocking vaccines aim to interrupt the transmission of malaria from one person to another.METHODSThe candidates R0.6C and ProC6C share the 6C domain of the Plasmodium falciparum sexual-stage antigen Pfs48/45. R0.6C utilizes the glutamate-rich protein (GLURP) as a carrier, and ProC6C includes a second domain (Pfs230-Pro) and a short 36-amino acid circumsporozoite protein (CSP) sequence. Healthy adults (n = 125) from a malaria-endemic area of Burkina Faso were immunized with 3 intramuscular injections, 4 weeks apart, of 30 μg or 100 μg R0.6C or ProC6C each adsorbed to Alhydrogel (AlOH) adjuvant alone or in combination with Matrix-M (15 μg or 50 μg, respectively). The allocation was random and double-blind for this phase I trial.RESULTSThe vaccines were safe and well tolerated with no vaccine-related serious adverse events. A total of 7 adverse events, mild to moderate in intensity and considered possibly related to the study vaccines, were recorded. Vaccine-specific antibodies were highest in volunteers immunized with 100 μg ProC6C-AlOH with Matrix-M, and 13 of 20 (65%) individuals in the group showed greater than 80% transmission-reducing activity (TRA) when evaluated in the standard membrane feeding assay at 15 mg/mL IgG. In contrast, R0.6C induced sporadic TRA.CONCLUSIONAll formulations were safe and well tolerated in a malaria-endemic area of Africa in healthy adults. The ProC6C-AlOH/Matrix-M vaccine elicited the highest levels of functional antibodies, meriting further investigation.TRIAL REGISTRATIONPan-African Clinical Trials Registry (https://pactr.samrc.ac.za) PACTR202201848463189.FUNDINGThe study was funded by the European and Developing Countries Clinical Trials Partnership (grant RIA2018SV-2311).
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An enveloped virus-like particle alum-adjuvanted cytomegalovirus vaccine is safe and immunogenic: A first-in-humans Canadian Immunization Research Network (CIRN) study.
Langley, JM, Gantt, S, Halperin, SA, Ward, B, McNeil, S, Ye, L, Cai, Y, Smith, B, Anderson, DE, Mitoma, FD
Vaccine. 2024;(3):713-722
Abstract
INTRODUCTION Cytomegalovirus (CMV) is the most common cause of congenital infection and affected children often have permanent neurodevelopmental sequelae, including hearing loss and intellectual disability. Vaccines to prevent transmission of CMV during pregnancy are a public health priority. This first-in-humans dose-ranging, randomized, placebo-controlled, observer-blinded study evaluated the safety and immunogenicity of an enveloped virus-like particle (eVLP) vaccine expressing a modified form of the CMV glycoprotein B (gB). METHODS Healthy CMV-seronegative 18 to 40-year-olds at 3 Canadian study sites were randomized to one of 4 dose formulations (0.5 µg, 1 µg, or 2 µg gB content with alum) or 1 µg gB without alum, or placebo, given intramuscularly on days 0, 56 and 168. Outcome measures were solicited and unsolicited adverse events (AE), severe AE, gB and AD-2 epitope binding antibody titers and avidity, and neutralizing antibody (nAb) titers to CMV measured in fibroblast and epithelial cell infection assays. RESULTS Among 125 participants, the most common solicited local and general AEs were pain and headache, respectively. A dose-dependent increase in gB binding, avidity and nAb titers was observed after doses 2 and 3, with the highest titers in the alum-adjuvanted 2.0 µg dose recipients after the third dose; in the latter 24 % had responses to the broadly neutralizing AD-2 epitope. Neutralizing activity to CMV infection of fibroblasts was seen in 100 % of 2.0 µg alum-adjuvanted dose recipients, and to epithelial cell infection in 31 %. Epithelial cell nAb titers were positively correlated with higher geometric mean CMV gB binding titers. CONCLUSIONS An eVLP CMV vaccine was immunogenic in healthy CMV-seronegative adults and no safety signals were seen. Alum adjuvantation increased immunogenicity as did higher antigen content and a three dose schedule. This phase 1 trial supports further development of this eVLP CMV vaccine candidate.
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Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Small Cell Lung Cancer Cohort.
Nishio, M, Murakami, S, Kawakami, H, Okishio, K, Tamiya, M, Kobayashi, H, Fujimoto, D, Sugawara, S, Kozuki, T, Oya, Y, et al
Cancer research communications. 2024;(1):226-235
Abstract
PURPOSE E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort. EXPERIMENTAL DESIGN Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers. RESULTS Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed. CONCLUSIONS E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy. SIGNIFICANCE This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.
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Phase 1/2 study of epacadostat in combination with durvalumab in patients with metastatic solid tumors.
Naing, A, Algazi, AP, Falchook, GS, Creelan, BC, Powderly, J, Rosen, S, Barve, M, Mettu, NB, Triozzi, PL, Hamm, J, et al
Cancer. 2023;(1):71-81
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BACKGROUND Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS The most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained. CONCLUSIONS Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect. CLINICAL TRIAL INFORMATION A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).