scholarly journals Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis

Leukemia ◽  
2020 ◽  
Vol 35 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Moshe Talpaz ◽  
Jean-Jacques Kiladjian
Keyword(s):  
Myeloproliferative Neoplasm ◽  
The United States ◽  
Janus Kinase ◽  
Phase Iii ◽  
Clinical Activity ◽  
Myeloproliferative Disease ◽  
Jak2 Mutation ◽  
Cell Counts ◽  
Cell Proliferation Inhibition ◽  
Marrow Fibrosis

AbstractMyeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1–2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1–2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke’s encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.

scholarly journals Management of thrombocythemia

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 227 ◽  
Author(s):  
Krisstina Gowin ◽  
Ruben Mesa
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasm ◽  
Symptom Assessment ◽  
Pegylated Interferon ◽  
Janus Kinase ◽  
Phase Iii ◽  
Thrombotic Risk ◽  
Telomerase Inhibitors ◽  
High Risk Disease ◽  
Low Dose Aspirin

Essential thrombocythemia is a clonal myeloproliferative neoplasm characterized by an elevated platelet count, the potential for both microvascular and macrovascular sequelae, and a risk for transformation to myelofibrosis or acute myeloid leukemia. A systematic and detailed initial analysis is essential for accurate diagnosis of essential thrombocythemia, as many etiologies are reactive and benign. Once a diagnosis has been made, risk stratification and symptom assessment are vital to guide the subsequent therapy. Treatment may be required in high-risk disease, such as in cases of advanced age or prior thrombotic events. Systemic therapy is aimed at reducing the thrombotic risk and includes daily low dose aspirin and in some patients, cytoreductive therapy.  Currently, the first line cytoreductive therapy includes hydroxyurea or pegylated interferon, with a phase III clinical trial underway comparing these two important agents. Anagrelide and clinical trials are reserved for refractory or intolerant patients. Looking to the future, new therapies including Janus kinase 2 (JAK2) and telomerase inhibitors are promising and may become valuable to the treatment armamentarium for those afflicted with essential thrombocythemia.

Additon of Low-Dose Interferon-alpha (LD-IFN-a) and Lenalidomide after Failure to a Combination of Thalidomide and Prednisone in Myelofibrosis with Myeloid Metaplasia (MMM).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4645-4645
Author(s):  
Lisa Reale ◽  
Emmanuel C. Besa
Keyword(s):  
Low Dose ◽  
Treatment Options ◽  
Objective Response ◽  
Clinical Activity ◽  
Spleen Size ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Cell Counts ◽  
Number Of Patients ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Primary myelofibrosis with myeloid metaplasia (MMM) is an uncommon myeloproliferative disease with limited effective treatment options. Therapy using thalidomide and prednisone (TP) or lenalidomide (L) show variable objective response of improvement of 22% in L to 62% in TP for anemia, 50% in L to 75% in TP for thrombocytopenia, and decrease in splenomegaly in 19% with TP to 33% with L and was well-tolerated. Additional clinical benefits show resolution of leukoerythroblastosis, and a decrease in medullary fibrosis and abnormal angiogenesis. Prolonged therapy with alpha-interferon (IFN-a) can improve hematopoiesis and reverse marrow fibrosis but doses used were poorly tolerated. Methods and Patients: Here we present five patients treated with combination T at 50 mg daily, P at 0.5 mg/kg po for 2 weeks then to 20 mg daily every other day for 3 months with no response. If this was tolerated, low-dose IFN-a (LD-IFN-a) at 1.5 million units sc. three times a week was added. The clinical and hematologic criterion of the European Myelofibrosis Network (EUMNET) were used as response criteria for our study. Three males, 2 females, age ranged from 60 to 85 years who had failed previous treatments from EPO, hydrea and transfusion support. White blood cell counts ranged from 4.3 to 29.7 B/L. Hemoglobin levels ranged from 7.3 to 11.6 g/dL. Platelets ranged from 13,000 to 283,000 B/L. Three patients developed iron overload from rbc transfusions and required iron-chelation therapy. Results: Of the five patients, one had a CR, one had a PR and two had regression that did not meet criteria for response and one unresponsive with no splenomegaly but stable disease. We noted that the addition of LD-IFN-a decreased the elevated WBC counts and Improvement in spleen size was seen about three months after the start of treatment. One patient had a CR in his WBC count approximately a month after starting therapy. The patient with CR had normal hemoglobin but had to discontinue after a year of T due to grade 2 neuropathy and was started on 10 mg/day of L while staying on IFN-a and P. She developed anemia and required transfusions for 3 months and achieved CR with shrinkage of her spleen size from 15 to 4 cm. The patient who was unresponsive to the combination of IFN-a- TP changed from T to L was stopped after the patient developed hemolytic anemia and splenomegaly. Conclusion: Addition of LD-IFN-a to the reported TP or L to replace T show clinical activity in patients with refractory MMM and is well tolerated with minimal toxicity. The use of lenalidomide may alleviate neuropathy but may induce hemolysis as an undesirable side effect. Further studies using low doses of these agents with varying activities to MMM in combination is needed to define their clinical use in the treatment of this disease entity in a much larger number of patients.

scholarly journals Temsirolimus: A Review of its Use in the Treatment of Advanced Renal Cell Carcinoma

2009 ◽  
Vol 1 ◽  
pp. CMT.S2349 ◽  
Author(s):  
Fanny Chan ◽  
Erika E. Samlowski ◽  
Wolfram E. Samlowski
Keyword(s):  
Renal Cancer ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
The United States ◽  
Treated Group ◽  
Phase Iii ◽  
Clinical Activity ◽  
Metastatic Renal Cancer

The mTOR (mammalian target of rapamycin) signaling pathway was discovered during studies of the immunosuppressive agent rapamycin. This pathway regulates cell growth, protein synthesis and angiogenesis in response to environmental factors. The mTOR complex-1 inhibitor temsirolimus was derived from rapamycin to have less immunosuppressive and improved solubility characteristics. The safety, tolerability and efficacy of temsirolimus have been well established in clinical trials. Drug related toxicity included rash, mucositis, asthenia, nausea, hyperglycemia, hypophosphatemia, anemia, and hypertriglyceridemia. An active and well-tolerated single agent dose is 25 mg i.v. weekly. A large Phase III trial in poor-prognosis patients with metastatic renal cancer compared i.v weekly temsirolimus administration to subcutaneous interferon alpha (IFNα), or a combination of temsirolimus plus IFNα. This study established that median overall survival was improved to 10.9 months in the temsirolimus group compared to 7.3 months in IFNα-treated group (0.73 hazard ratio for death; 95% confidence interval [CI], 0.58 to 0.92; P = 0.008). A modest objective response rate of 8.6%, 4.8%, and 8.1%, respectively was observed in the three groups, associated with a median time to treatment failure of 3.8 months for temsirolimus alone, 1.9 months for IFNα, and 2.5 months for the combination. These results led to approval of temsirolimus for the treatment of renal cancer in the United States. Temsirolimus is clearly indicated for first-line therapy of Motzer “poor risk” renal cancer and aggressive non-clear cell renal cancer. Temsirolimus may be useful after failure of VEGF tyrosine kinase inhibitors. Clinical activity in other tumor types, such as endometrial cancer has been observed. Temsirolimus is therefore an important new agent for cancer treatment.

Essential Thrombocythemia: A Review of Diagnostic and Pathologic Features

2006 ◽  
Vol 130 (8) ◽  
pp. 1144-1150
Author(s):  
Steven Sanchez ◽  
April Ewton
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Disorder ◽  
Janus Kinase ◽  
Data Sources ◽  
Bone Marrow Fibrosis ◽  
Jak2 Mutation ◽  
Pathologic Features ◽  
Laboratory Features ◽  
Chronic Myeloproliferative Disorder ◽  
Marrow Fibrosis

Abstract Context.—Essential thrombocythemia (ET) is a chronic myeloproliferative disorder (CMPD) characterized predominately by thrombocytosis and abnormal megakaryocyte proliferation. The current diagnostic criteria require a combination of clinical, histologic, and cytogenetic data. The diagnosis relies largely on exclusion of other causes of thrombocytosis. Objective.—Describe historical, clinical, and laboratory features of ET in order to understand, clarify, and more accurately diagnose this entity. Data Sources.—Review contemporary and historical literature on ET and other causes of thrombocytosis. Conclusions.—ET is a relatively indolent and often asymptomatic CMPD that is characterized primarily by a sustained elevation in platelets ≥600 × 103/μL (≥600 × 109/L), proliferating enlarged and hyperlobated megakaryocytes, and minimal to absent bone marrow fibrosis. Significant changes and revisions to the diagnostic requirements and criteria for ET have occurred during the last 30 years. Recently, a mutation in the Janus kinase 2 (JAK2) gene has been found in a significant number of cases of ET and other CMPDs. In up to 57% of ET cases, a mutation in the JAK2 gene can be detected. In the absence of a JAK2 mutation and features of another CMPD, the diagnosis of ET remains a diagnosis of exclusion after other causes of thrombocytosis have been excluded.

Hemizygous/Homozygous and Heterozygous JAK2 Mutation Detected in Plasma of Patients with Myeloproliferative Diseases: Correlation with Clinical Behavior.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2593-2593
Author(s):  
W. Ma ◽  
H. Kantarjian ◽  
I. Jilani ◽  
M. Gorre ◽  
F. Giles ◽  
...  
Keyword(s):  
Lymphoid Cells ◽  
Janus Kinase ◽  
Heterozygous Mutation ◽  
Homozygous Mutation ◽  
Jak2 Mutation ◽  
Cell Counts ◽  
Number Of Patients ◽  
Significant Difference ◽  
Myeloproliferative Diseases ◽  
Chronic Myeloproliferative Diseases

Abstract The Val617Phe mutation in JAK2 (Janus kinase) has been reported in approximately 90% of patients with polycythemia vera (PV) and in almost 40% of patients with essential thrombocythemia (ET) or idiopathic myelofibrosis (IMF). JAK2 is a cytoplasmic tyrosine kinase that binds to growth factor receptors and phosphorylates several downstream proteins that are involved in cell proliferation and growth. The Val617Phe mutation can be detected in circulating granulocytes. Homozygous as well as hemizygous (deletion of 1 allele and mutation in the second) mutations have been reported. The clinical importance of hemi/homozygous as compared to heterozygous mutation is not known. Furthermore, the presence of normal lymphoid cells or non-neoplastic cells in samples makes it difficult to be certain whether the mutation is homozygous in a subpopulation of cells, or heterozygous. Since we have shown that the plasma of patients with leukemia is enriched with leukemia-specific DNA, RNA, and protein, we tested the possibility of detecting JAK2 mutations in patients with chronic myeloproliferative diseases using RNA from peripheral blood (PB) plasma rather than cells. In this study, PB plasma was obtained from 39 patients with IMF, 16 with PV, 8 with ET, and 23 with other chronic myeloproliferative disease not otherwise classified (MPD-NC). Bi-directional direct sequencing of RNA extracted from plasma was used to detect mutations in the JAK2 transcript. The Val617Phe mutation was detected in 88% of PV patients, of whom 50% (44% of all samples) were hemi/homozygous. This mutation was detected in 56% of IMF patients, 41% of whom were hemi/homozygous. The number of patients with ET was small, but 25% (2 patients) had hemi/homozygous mutation. 26% of the patients with MPD-NC had JAK2 mutation; of these, 33% had hemi/homozygous mutation. The plasma of 31 normal control individuals showed no evidence of mutation and mixing studies showed that the Val617Phe mutation was easily detectable when lysate from HEL cell line (homozygous for the mutation) were mixed with plasma down to 5 cell/1ml plasma. Patients with hemi/homozygous mutation had significantly larger spleens (P=0.0001), increased white cell counts (P=0.001), and increased monocyte counts in bone marrow (P=0.03). We cannot demonstrate statistically significant difference in survival between hemi/homozygous and heterozygous, however, the number of cases is too small. The presence of mutation (hemi/homozygous or heterozygous) was associated with better overall survival in patients <65 years of age irrespective of the type of MPD (n=54, P=0.05). Patients with MPD-NC had more aggressive disease than other patients (ET, PV and IMF) (P=0.02), but presence of the Val617Phe mutation was associated with longer survival in the MPD-NC group (P=0.05). This does not only confirm that PB plasma is a reliable source for detecting JAK2 mutations, but also show that this mutation is often hemi/homozygous. The presence of JAK2 mutation as detected in plasma of patients with various types of chronic myeloproliferative diseases is associated with longer survival in patients <65 years and is also a favorable prognostic factor in patients with MPD-NC.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

scholarly journals Update on the therapeutic management of patients with either psoriatic arthritis or ulcerative colitis: focus on the JAK inhibitor tofacitinib

2021 ◽  
Vol 13 ◽  
pp. 1759720X2097777
Author(s):  
Maria Sole Chimenti ◽  
Paola Conigliaro ◽  
Livia Biancone ◽  
Roberto Perricone
Keyword(s):  
Ulcerative Colitis ◽  
Psoriatic Arthritis ◽  
Janus Kinase ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Immune Mediated ◽  
Significant Burden ◽  
Phase Iii Trials ◽  
Disease Modifying Agents ◽  
Interleukin Inhibitors

Psoriatic arthritis (PsA) and ulcerative colitis (UC) are immune-mediated diseases that cause significant burden worldwide. Recent advances in their management have improved patient outcomes. However, significant unmet needs still remain as not all patients respond to current treatments, and patients may lose responsiveness over time. An improved understanding of the pathophysiology of these diseases has brought about the development of novel disease-modifying agents, including interleukin inhibitors and, more recently, Janus kinase (JAK) inhibitors. With the approval of tofacitinib for the treatment of adults with active PsA and in adult patients with moderately-to-severely active UC, JAK inhibitors have recently entered the treatment armamentarium for PsA and UC. A number of other JAK inhibitors are also undergoing clinical development and are currently in phase III trials. This review provides an overview of the current therapeutic options for PsA and UC, with a focus on the JAK inhibitors.

Phase III Trials in Pancreatic Cancer in the United States

2010 ◽  
Vol 9 (1) ◽  
pp. 59-60
Author(s):  
Edward Chu ◽  
David Cunningham ◽  
David Watkins
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
The United States ◽  
Phase Iii ◽  
Phase Iii Trials

scholarly journals Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2440
Author(s):  
Francesco Spagnolo ◽  
Bruna Dalmasso ◽  
Enrica Tanda ◽  
Miriam Potrony ◽  
Susana Puig ◽  
...  
Keyword(s):  
Real World ◽  
Response Rate ◽  
Suppressor Gene ◽  
Phase Iii ◽  
Clinical Activity ◽  
P Value ◽  
Pathogenic Variants ◽  
Phase Iii Trials ◽  
The Difference ◽  
First Time

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

A randomized phase III, two-arm trial of paclitaxel, carboplatin, and maintenance letrozole versus letrozole monotherapy in patients with stage II-IV, primary low-grade serous carcinoma of the ovary or peritoneum.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5601-TPS5601
Author(s):  
Amanda Nickles Fader ◽  
Lilian Tran Gien ◽  
Austin Miller ◽  
Al Covens ◽  
David Marc Gershenson
Keyword(s):  
Clinical Trial ◽  
Maintenance Therapy ◽  
Aromatase Inhibitor ◽  
The United States ◽  
Stage Ii ◽  
Phase Iii ◽  
Serous Carcinoma ◽  
Low Grade ◽  
Information Time ◽  
Carcinoma Of The Ovary

TPS5601 Background: Low-grade serous carcinoma of the ovary or peritoneum (LGSOC) is a rare subtype of epithelial carcinoma. Differences in epidemiology, pathogenesis, disease presentation, and clinical outcomes have been characterized between women diagnosed with LGSOC and those with the p53-driven high-grade serous carcinoma (HGSOC). Ultimately, patients with LGSOC should be treated differently than those with HGSOC. Several studies suggest that LGSOC is relatively chemoresistant and that most tumors robustly express estrogen and progesterone receptors. Recently, retrospective reports suggest that utilization of the aromatase inhibitor, letrozole, as monotherapy or in addition to platinum/taxane-based chemotherapy in those with primary advanced-stage LGSOC results in preliminarily promising survival outcomes. Methods: This study is a two-arm, randomized, open-label, Phase III clinical trial. The primary objective is to assess whether letrozole monotherapy (2.5 mg po daily) is non-inferior to carboplatin (AUC 5-6) and paclitaxel (175 mg/m2) followed by letrozole maintenance therapy with respect to progression free survival in women with primary, Stage II-IV LGSOC who have undergone an attempt at maximal surgical cytoreduction. Secondary endpoints include incidence of adverse events, objective response rate in those with measurable disease after surgery, response duration, overall survival, and adherence to letrozole maintenance therapy. Study subjects must have undergone a bilateral salpingo-oophorectomy, and p53 IHC testing of tumors is required to rule out those with aberrant p53 expression commonly observed in HGSOC tumors. Study strata include residual disease status and country of enrollment. Four hundred and fifty patients will be enrolled in the United States, Canada and South Korea through the NRG Oncology trials network. Correlative aims include analyzing the association of ER/PR tumoral expression with aromatase inhibitor therapy response and determining ESR1 mutational status in those who develop letrozole resistance. The study includes two interim analyses; at 20% information time, a futility analysis will be conducted, and at 40% information time, both efficacy and futility will be assessed. This is one of the first randomized trials performed in women with primary, advanced LGSOC, and the study is open with 71 patients enrolled at the time of abstract submission. Clinical trial information: NCT04095364.

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