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A Phase I Study on the Tolerance, Pharmacokinetics and Pharmacodynamics of YL-13027

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ClinicalTrials.gov Identifier: NCT03869632
Recruitment Status : Not yet recruiting
First Posted : March 11, 2019
Last Update Posted : March 11, 2019
Sponsor:
Information provided by (Responsible Party):
Shanghai YingLi Pharmaceutical Co. Ltd.

Brief Summary:
Protocol YL-13027-001 is a phase I open-label, first in human, dose escalation study to assess the tolerability, pharmacokinetics (PK) and efficacy of YL-13027 in patients with advanced solid tumor.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Drug: YL-13027 Phase 1

Detailed Description:

This is a two-part study comprised of a dose escalation part and a dose expansion part.In the dose escalation part single patient cohorts will be dosed until a single related toxicity of Grade ≥ 2 or a Dose Limiting Toxicity (DLT) is observed. If this occurs, the study will switch to a conventional oncology 3+3 design (3 patients per dose cohort, with the potential to add an additional 3 patients if toxicity is observed) and escalation will continue until the maximum tolerated dose (MTD) is reached and a recommended Phase II (RP2D) dose is determined. Once the MTD is established a separate dose expansion part will enroll up total additional 16 patients at the RP2D.

In this clinical trial, YL-13027 is given orally once daily. A treatment cycle is defined as 28 days. YL-13027 was given until disease progression, unacceptable toxicity, or withdrawal from the study. The protocol was initiated with a single-patient cohort, treated with oral YL-13027 60 mg once daily (QD). Subsequent cohorts used a 3+3 design and evaluated doses of 40-320mg QD. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according toRECIST v1.1.


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Study Type : Interventional
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description: dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Single Arm, Open, Single and Multiple Dosing and Incremental Dose Study of YL-13027 to Evaluate the Tolerance, Pharmacokinetics and Pharmacodynamics in Patients With Advanced Solid Tumor
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2020

Arm Intervention/treatment
Experimental: YL-13027

YL-13027 is a selective inhibitor of the beta isoform of transforming growth factor (TGF-β).

YL-13027 for clinical use is presented as a sterile tablets at 10 mg, or 50 mg doses. The drug product is intended for oral administration.Preset cohorts of 3-6 subjects will be enrolled sequentially at doses of 60, 120, 180, 240, 300, and 360 mg/day.

Drug: YL-13027
YL-13027 is a new type of TGF-βselective inhibitor which differs structurally from Galunisertib and its analogs, showing high potency against TGF-β, but with markedly improved selectivity. This higher selectivity for TGF-β may decrease the risk of serious infection seen with Galunisertib and especially with duvelisib due to strong immune suppression.Preclinical evaluation has demonstrated improved efficacy and safety for YL-13027 compared to Galunisertib.




Primary Outcome Measures :
  1. Dose limited toxicities evaluated with NCI-CTC AE v5.0 [ Time Frame: within 28 days after the first dose ]
    Incidence of dose limited toxicities and associated dose of YL-13027

  2. Adverse events evaluated by NCI CTCAE v5.0 [ Time Frame: from the first dose to within 30 days after the last dose ]
    Incidence of adverse events and associated dose of YL-13027

  3. Plasma concentration of YL-13027 [ Time Frame: within 56 days after the first dose ]
    This composite endpoint will measure the plasma concentration of YL-13027

  4. Objective response rate [ Time Frame: within 30 days after the last dose ]
    the proportion of subjects who have a Complete Response or Partial Response

  5. Disease control rate [ Time Frame: within 30 days after the last dose ]
    the proportion of subjects who have a Complete Response or Partial Response



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1.Males and/or females age from 18 to 75; 2.Histologically or cytologically confirmed patients with advanced malignant solid tumors, eligible patients must have failed standard treatment, no standard treatment, or not suitable for standard treatment at this stage as determined by the investigator; 3.In the dose escalation portion, both measurable and non-measurable tumor lesions were acceptable according to RECIST1.1 criteria;There was at least one measurable tumor lesion in the dose extension portion; 4.Eastern Cooperative Oncology Group performance status of 0 to 1; 5.Life expectancy of at least 3 months; 6.Acceptable hematologic status: Absolute neutrophil count(ANC)≥1.0×109/L; Platelet count(PLT)≥70×109/L; Hemoglobin(Hb)≥80 g/L; Total bilirubin(TBIL)≤1.5×Upper limit of normal value(ULN); Alanine aminotransferase(ALT)≤2.5×ULN; Aspartate aminotransferase(AST)≤2.5×ULN; Creatinine(Cr)≤1.5×ULN; Creatinine clearance ≥50ml/min;Left Ventricular Ejection Fractions(LVEF)≥50%; QTcF:male/ female<450 ms,<470 m; 7.The washout period from the last time accepting any anti-tumor treatment (including radiation therapy, chemotherapy, hormone therapy, surgery, or molecular targeted therapy) to participating in this test should be 4 weeks or more.The washout period of oral fluorouracil should be 2 weeks or more, and that of mitomycin and nitrosocarbamide should be 6 weeks or more; 8.Fertile male and female must agree to use medically approved contraceptives during the study and within 6 months after the last dose of the study; 9.Female who is capable of conceiving:Blood pregnancy tests should be negative 7 days before the first dose; Patients cannot breastfeed, if the subject has stopped breastfeeding at the time of study entry, the cessation of breastfeeding must be from the day of first dose to more than 30 days after the last dose; 10.The last time participate in an investigational drug or device study should be more than one month prior to study entry; 11.According to the judgment of the researcher, he/she has high compliance and is willing to complete the experiment and comply with the protocol 12.Voluntary participation in this clinical trial, understanding of the study procedures and the ability to sign informed consent forms (ICFs).

Exclusion Criteria:

- 1.There are third interstitial effusions (such as massive pleural effusion and ascites) which can not be controlled by drainage or other methods; 2.Within 3 months before the first dose, grade 3 or grade 4 gastrointestinal bleeding or varicose bleeding and requiring blood transfusion or endoscopic or surgical intervention has happened; 3.Medical history of difficulty in swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product; 4.Patients with central nervous system (CNS) involvement; 5.Known infection with human immunodeficiency virus (HIV), hepatitis B virus(HBV), or hepatitis C virus (HCV); 6.History of immunodeficiency, including HIV positive test, other acquired or congenital immunodeficiency disorders, organ transplantation or allogeneic bone marrow transplantation; 7.Exists moderate or severe heart disease:

  1. Within 6 months before the first dose,myocardial infarction, angina, grade III/IV congestive heart failure, pericardial effusion, uncontrollable severe hypertension (up to 150/90 mmHg or less)
  2. ECG abnormalities with clinical significance: symptomatic or persistent atrial or ventricular arrhythmias, degree II or III atrioventricular block, bundle branch block, ventricular hypertrophy;
  3. The echocardiogram shows significant abnormalities: For example, moderate or severe heart valve function defects are assessed according to the normal lower limit of the institution;Patients with minor or mild valve regurgitation (tricuspid, pulmonary, mitral, or aortic) can be included in this study
  4. Laboratory examination shows brain natriuretic peptide or troponin T levels increases
  5. Various factors that may increase the risk of QTcF prolonging or arrhythmia events
  6. For example, hypokalemia, congenital long QT syndrome, may prolong the QT interval of various combined drugs, etc.
  7. Predisposition factors cause the development of ascending aorta or aortic arch aneurysm: For example, marfan syndrome, CT records of the history of cardiac vascular injury;
  8. History of heart or aortic surgery. 8. Patients with central nervous system metastasis; 9. At the beginning of the study, the unrecovered toxicity of the previous treatment exceeded CTCAE5.0 grade 1(except for hair loss); 10. Previously treated with TGF-β inhibitors; 11.According to the judgement of the researcher,there are concomitant diseases that seriously endanger the safety of patients or affect the completion of the study (such as severe hypertension, diabetes, thyroid diseases, etc.).

12.The researchers think the subjects are not suitable for this study for other reasons.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03869632


Contacts
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Contact: Hanying Bao, MD,PhD 86 21-51370693 hybao@yl-pharma.com
Contact: Yuanyuan Xu, M.S. 86 21-51320088 ext 8588 yyxu@yl-pharma.com

Locations
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China, Shanghai
Shanghai East Hospital Not yet recruiting
Shanghai, Shanghai, China, 200123
Contact: Jin Li, PhD       lijin@csco.org.cn   
Contact: Ye Guo, PhD         
Principal Investigator: Jin Li, PhD         
Sub-Investigator: Ye Guo, PhD         
Sponsors and Collaborators
Shanghai YingLi Pharmaceutical Co. Ltd.
Investigators
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Study Director: Hanying Bao, PhD Shanghai YingLi Pharmaceutical Co. Ltd.

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Responsible Party: Shanghai YingLi Pharmaceutical Co. Ltd.
ClinicalTrials.gov Identifier: NCT03869632     History of Changes
Other Study ID Numbers: YL-13027-001
First Posted: March 11, 2019    Key Record Dates
Last Update Posted: March 11, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shanghai YingLi Pharmaceutical Co. Ltd.:
YL-13027
Advanced Solid Tumor