論文

Background: Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented. Methods: Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. Results: Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%–46.0%) in cohort A and 34.9% (95% CI, 23.3%–48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1–8.1) in cohort A and 4.1 months (95% CI, 2.1–18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4–58.0) in cohort A and 47.0 months (95% CI, 19.2–NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response. Conclusions: Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC. Clinical Trial Registry Information: ClinicalTrials.gov, NCT02460198

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.

Background: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study. Methods: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1–2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1–2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients. Findings: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7–49·8]), median overall survival was not reached (NR; 95% CI 49·2–NR) with pembrolizumab vs 36·7 months (27·6–NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53–1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4–38·1) with pembrolizumab versus 8·2 months (6·1–10·2) with chemotherapy (HR 0·59, 95% CI 0·45–0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. Interpretation: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Funding: MSD.

Background: Results from the phase III KEYNOTE-177 study established pembrolizumab as a new first-line standard of care for microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Previous results from KEYNOTE-177 showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with pembrolizumab versus chemotherapy ± bevacizumab/cetuximab in MSI-H/dMMR mCRC. Results after >5 years of follow-up are reported. Patients and methods: Adults with untreated MSI-H/dMMR mCRC were randomly assigned 1 : 1 to receive pembrolizumab 200 mg intravenously every 3 weeks or chemotherapy. Patients assigned to chemotherapy could cross over to pembrolizumab after centrally confirmed progressive disease. Dual primary endpoints were PFS per RECIST v1.1 and overall survival (OS). Secondary endpoints included duration of response and safety. Results: At data cut-off (17 July 2023), median follow-up was 73.3 months (range, 64.9-89.2 months). Overall, 307 patients were assigned to receive pembrolizumab (n = 153) or chemotherapy (n = 154). Fifty-seven (37.0%) patients assigned to chemotherapy crossed over to pembrolizumab per protocol; 39 (25.3%) received a programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitor off protocol (effective crossover rate, 62%). Median OS was 77.5 months with pembrolizumab versus 36.7 months with chemotherapy (hazard ratio, 0.73; 95% confidence interval 0.53-0.99); 5-year OS rates were 54.8% versus 44.2%. Median PFS was 16.5 months with pembrolizumab and 8.2 months with chemotherapy (hazard ratio, 0.60; 95% confidence interval 0.45-0.79). Median duration of response was 75.4 months (range, 2.3+ to 80.1+ months) with pembrolizumab versus 10.6 months (range, 2.8 to 71.5+ months) with chemotherapy. Compared with chemotherapy, fewer patients in the pembrolizumab arm experienced adverse events (80% versus 99%; grade 3-5, 22% versus 67%). Conclusions: With >5 years of follow-up, responses to pembrolizumab remained durable. Median OS was more than twice as long in patients treated with pembrolizumab versus chemotherapy in first line despite an effective crossover rate of 62%. Pembrolizumab remains a standard of care for MSI-H/dMMR mCRC.

Background: Tusamitamab ravtansine (SAR408701) is an immunoconjugate that binds carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers its cytotoxic payload to target cells. Here, we report findings from three dosing regimens of tusamitamab ravtansine administration in Japanese adults with advanced malignant solid tumors. Methods: Japanese adults (aged ≥ 20 years) with CEACAM5-expressing malignant solid tumors were enrolled in this Phase 1, open-label, non-randomized, dose-escalation evaluation of tusamitamab ravtansine in three parts: (i) main dose-escalation part with every two weeks (Q2W) administration, (ii) loading dose (LD) part with Q2W administration with a LD at Cycle 1 (C1) only, and (iii) dose-escalation every three weeks (Q3W) part. Primary objectives were to evaluate the tolerability and safety of tusamitamab ravtansine. Results: Nine patients were enrolled in the main dose-escalation part, 16 patients in the dose-escalation bis part with LD, and nine patients in the dose-escalation Q3W part. Administration of tusamitamab ravtansine resulted in a manageable safety profile with no dose-limiting toxicities reported during the observation period except for two events during dose-escalation bis Q2W part. Most common adverse events (AEs) were corneal events, gastrointestinal disorders, and metabolic events. After first administration, tusamitamab ravtansine exposure was dose proportional over the dose range 80–170 mg/m2. Best overall response (BOR) was stable disease, observed in all three parts; confirmed response was not observed at any dose level. Conclusion: Tusamitamab ravtansine demonstrated a tolerable safety profile at a dose of 80–170 mg/m2 in three different administration schedules in Japanese adults with metastatic solid tumors.

BACKGROUND: Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. PATIENTS AND METHODS: Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. RESULTS: Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. CONCLUSIONS: FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort. Clinical Trial Registration:jRCT2011200023 (ClinicalTrials.gov).

Abstract Background Physical activity (PA) has been consistently associated with improved cancer outcomes across multiple epidemiological studies. While the evidence for clinical benefits is strong, the underlying molecular mechanisms remain poorly understood. Recent technological advances now enable both continuous monitoring of PA through wearable devices and comprehensive molecular profiling through multi-omics approaches, including whole-genome sequencing (WGS)-based molecular residual disease (MRD) detection. This review examines current evidence regarding PA’s effects on cancer biology and introduces the LIFELOG study, which aims to address critical knowledge gaps in this field. Methods We review the current literature on PA and cancer with emphasis on molecular mechanisms, and present the design of the LIFELOG study, an ancillary study to MONSTAR-SCREEN-3. The LIFELOG study will enroll 170 post-surgical cancer patients who will wear the mSafety™ wrist device for continuous PA monitoring. We will investigate associations between PA metrics and multi-omics profiles including WGS-based MRD detection, transcriptome analyses, plasma proteomics, and gut microbiome analyses. The feasibility phase has already begun with encouraging preliminary results regarding device compliance and data quality. Discussion Despite substantial evidence supporting PA’s benefits in cancer prevention and survivorship, understanding which specific PA characteristics most effectively influence cancer outcomes remains unclear. The LIFELOG study represents the first comprehensive analysis integrating continuous PA monitoring with molecular profiling in cancer patients. By examining relationships between PA patterns and both MRD dynamics and multi-omics profiles, we aim to identify molecular mechanisms underlying exercise benefits and potentially guide development of evidence-based, precision PA interventions for cancer survivorship. Trial Registration This ancillary study (Institutional Review Board number: 2024-111, approved on November 18, 2024) is conducted under the MONSTAR-SCREEN-3 trial platform, which is registered in the UMIN Clinical Trials Registry (UMIN000053975, registered on March 27, 2024).

Background: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished. Patients and Methods: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model. Results: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups. Conclusion: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment. Clinical Trial Number: UMIN000028616

With the increasing importance of nuclear medicine therapy in overall cancer care and the introduction of 177Lu-PSMA-617 to Japan being imminent, the Policy Recommendations for Promoting Nuclear Medicine Therapy in Japan from the Working Group for Promoting Nuclear Medicine Therapy of the Japan Society of Clinical Oncology (JSCO) aim to identify issues related to nuclear medicine therapy and propose measures to address them, in order to further advance nuclear medicine therapy in Japan. It is necessary to create an environment in which each medical institution can proactively introduce nuclear medicine therapy by taking measures that target discharge criteria, medical fees, and human resource development and link them organically. The Working Group believes that it is necessary to continue examining long-term issues taking into account the changes that have occurred since the introduction of 177Lu-PSMA-617, as well as trends in nuclear medicine therapy other than 177Lu-PSMA-617 that are expected to be introduced in the future. In addition, as the “Action Plans for Promoting the Production and Use of Medical Radioisotopes” have been formulated and the advancement of nuclear medicine therapy has become one of the nation’s major policy priorities, JSCO will continue to actively work with relevant ministries and local governments to resolve the various issues of nuclear medicine therapy, including the smooth introduction of 177Lu-PSMA-617.

Background: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. Patients and methods: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. Results: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. Conclusions: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Objective: Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)-induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype-based FP dosing strategy. Patients and Methods: The current study aimed to investigate their impact on FP-related toxicities in an Asian population using genome-wide association study (GWAS) data set from 1364 patients with colon cancer. Results: Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP-related toxicities; however, none of these variants revealed a significant correlation with FP-related toxicities. Conclusion: These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP-related toxicities in an Asian population.

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition whose population-level characteristics and clinical concordance in Japan remain incompletely defined. We analyzed whole-genome sequencing data from 49,982 participants in the Tohoku Medical Megabank (TMM) cohort to characterize the prevalence, mutational spectrum, age dependency, and clinical relevance of CHIP. CHIP mutations were detected in 1234 individuals (2.5%), comprising 1413 variants across 1015 loci. DNMT3A and TET2 were the most frequently mutated genes, whereas ASXL1 and PPM1D mutations were less prevalent than reported in Western cohorts. Four recurrent CHIP candidate loci (ZNF318, SMC3, CBL, and GNAS) were identified, most of which were predicted to be oncogenic. Comparison with TOPMed and UK Biobank datasets demonstrated overall concordance in variant prevalence, with differences observed for selected driver mutations. dN/dS analysis indicated positive selection in the majority of CHIP-associated genes. Concordance with clonal hematopoiesis (CH) mutations detected in cancer patients was evaluated using data from the MONSTAR-SCREEN-2 study with paired leukocyte sequencing. When focusing on genes in which CHIP mutations have been reported, 66% were confirmed as CH, yielding a positive predictive value of 66% and a negative predictive value of 76%. CHIP prevalence increased significantly with age, exceeding 5% in individuals aged ≥ 70 years, with an estimated 3.4% increase per additional year of age. Higher variant allele frequency mutations showed a slightly stronger age association. These findings define the landscape of CHIP in the Japanese population and clarify its relationship to CH detected by cancer-focused liquid biopsy assays.

Tumor-informed circulating tumor DNA (ctDNA) enables detection of molecular residual disease (MRD) after curative resection of colorectal cancer (CRC), but whether early intervention improves outcomes remains uncertain. ALTAIR was a randomized, double-blind, phase 3 trial embedded in the CIRCULATE-Japan platform evaluating a post-adjuvant ctDNA surveillance strategy with treatment initiation upon molecular recurrence. Patients with resected stage 0–IV CRC who became ctDNA positive after completion of standard-of-care therapy and had no radiological evidence of disease were randomly assigned (1:1) to receive trifluridine/tipiracil (FTD/TPI) or placebo for 6 months. The primary endpoint was investigator-assessed disease-free survival (DFS). Between July 2020 and June 2023, 243 patients were randomized to FTD/TPI (n = 122) or placebo (n = 121). Median DFS was 9.30 months with FTD/TPI and 5.55 months with placebo (hazard ratio = 0.79, 95% confidence interval: 0.60–1.05, P = 0.107), and the primary endpoint was not met. FTD/TPI increased grade 3 or higher hematologic adverse events (73.0% versus 3.3%) without new safety signals. These findings indicate that post-adjuvant intervention with FTD/TPI did not significantly improve DFS in ctDNA-positive patients without radiological disease. ClinicalTrials.gov identifier: NCT04457297.