A Phase I Study of YY-20394 in Patients With B Cell Hematologic Malignancies
NCT ID: NCT03757000
Last Updated: 2018-12-10
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE1
42 participants
INTERVENTIONAL
2017-12-25
2019-05-30
Brief Summary
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Detailed Description
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In the dose escalation part single patient cohorts will be dosed until a single related toxicity of Grade ≥ 3 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 12 patients at the RP2D.
In this clinical trial, YY-20394 is given orally once daily. A treatment cycle is defined as 28 days. YY-20394 was given until disease progression, unacceptable toxicity, or withdrawal from the study. The protocol was initiated with a single-patient cohort, treated with oral YY-20394 20 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 v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria.
Conditions
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Keywords
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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YY-20394
YY-20394 is a selective inhibitor of the delta isoform of phosphatidylinositol 3- kinase (PI3Kδ).
YY-20394 for clinical use is presented as a sterile tablets at 20 mg, or 100 mg doses. The drug product is intended for oral administration.Preset cohorts of 3-6 subjects will be enrolled sequentially at doses of 20, 40, 80, 140, 200, 260 and 320 mg/day.
YY-20394
YY-20394 is a new type of PI3K-δ selective inhibitor which differs structurally from idelalisib and its analogs, showing high potency against PI3Kδ, but with markedly improved selectivity (\>1,000-fold selectivity for PI3K-δ versus PI3Kγ). This higher selectivity for PI3Kδ may decrease the risk of serious infection seen with idelalisib and especially with duvelisib due to strong immune suppression.Preclinical evaluation has demonstrated improved efficacy and safety for YY-20394 compared to idelalisib.
Interventions
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YY-20394
YY-20394 is a new type of PI3K-δ selective inhibitor which differs structurally from idelalisib and its analogs, showing high potency against PI3Kδ, but with markedly improved selectivity (\>1,000-fold selectivity for PI3K-δ versus PI3Kγ). This higher selectivity for PI3Kδ may decrease the risk of serious infection seen with idelalisib and especially with duvelisib due to strong immune suppression.Preclinical evaluation has demonstrated improved efficacy and safety for YY-20394 compared to idelalisib.
Eligibility Criteria
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Inclusion Criteria
2. Histologically or cytologically confirmed B cell malignancies
3. Eastern Cooperative Oncology Group performance status of 0 to 2
4. Life expectancy of at least 3 months
5. At least one measurable lesion by Computed Tomography(CT) or Magnetic Resonance Imaging(MRI) according to, which is not in irradiated area (only for expansion phase)
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)≤1.5×ULN; Aspartate aminotransferase(AST)≤1.5×ULN; Blood urea nitrogen(BUN)≤1×ULN; Creatinine(Cr)≤1×ULN; Left Ventricular Ejection Fractions(LVEF)≥50%； QTcF：male\<450 ms,female\<470 ms
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.
8. The last time participate in an investigational drug or device study should be more than one month prior to study entry.
9. Ability to understand the purposes and risks of the study
10. Availability of the signed informed consent forms (ICFs) approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of the study site obtained before entering the study.
Exclusion Criteria
2. Any anti-tumor treatment, within 4 weeks prior to study entry.
3. There are third interstitial effusions (such as massive pleural effusion and ascites) which can not be controlled by drainage or other methods.
4. The dosage of steroid hormone (prednisone equivalent) was greater than 20mg/ days, and lasted for more than 14 days.
5. 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.
6. During the study period, drugs that may prolong the QT (such as anti arrhythmic drugs) could not be interrupted.
7. Patients with central nervous system (CNS) involvement.
8. Allergy, or known to be allergic to the drug.
9. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy(such as pneumonia).
10. Known infection with human immunodeficiency virus (HIV), hepatitis B virus(HBV), or hepatitis C virus (HCV).
11. History of immunodeficiency, including HIV positive test, other acquired or congenital immunodeficiency disorders, organ transplantation or allogeneic bone marrow transplantation.
12. Autologous hematopoietic stem cell transplantation was received within 90 days before the first dose treatment.
13. Has suffered from any heart disease, including: (1) angina pectoris; (2) medicated or clinically significant arrhythmia; (3) myocardial infarction; (4) heart failure; (5) any other heart disease judged by the researchers not suitable for the test.
14. The baseline pregnancy test was positive in pregnant women, lactating women or fertile women.
15. 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.).
16. Receiving granulocyte colony-stimulating factor(GCSF) or blood transfusion within 7 days before screening.
17. Patients suffering from other primary malignant tumors in the past 5 years.
18 Years
ALL
No
Sponsors
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Shanghai YingLi Pharmaceutical Co. Ltd.
INDUSTRY
Responsible Party
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Principal Investigators
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Hanying Bao, PhD
Role: STUDY_DIRECTOR
Shanghai YingLi Pharmaceutical Co. Ltd.
Locations
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Peking Cancer Hospital
Beijing, Beijing Municipality, China
Jiangsu Province Hospital
Nanjing, Jiangsu, China
Hematology Hospital of Chinese Academy of Medical Sciences
Tianjin, Tianjin Municipality, China
Countries
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Central Contacts
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Facility Contacts
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Yuqin Song, MD,PhD
Role: primary
Meifeng Tu, MD,PhD
Role: backup
Jiangyong Li, MD,PhD
Role: primary
Wei Xu, MD,PhD
Role: backup
Lugui Qiu, MD,PhD
Role: primary
Junyuan Qi, MD,PhD
Role: backup
References
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Eisenreich A, Rauch U. PI3K inhibitors in cardiovascular disease. Cardiovasc Ther. 2011 Feb;29(1):29-36. doi: 10.1111/j.1755-5922.2010.00206.x.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004 Apr 23;304(5670):554. doi: 10.1126/science.1096502. Epub 2004 Mar 11. No abstract available.
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008 Sep 18;27(41):5497-510. doi: 10.1038/onc.2008.245.
Kong D, Yamori T. Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy. Cancer Sci. 2008 Sep;99(9):1734-40. doi: 10.1111/j.1349-7006.2008.00891.x. Epub 2008 Jul 4.
Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-7. doi: 10.1182/blood-2013-11-535047. Epub 2014 Mar 10.
Flinn IW, Kahl BS, Leonard JP, Furman RR, Brown JR, Byrd JC, Wagner-Johnston ND, Coutre SE, Benson DM, Peterman S, Cho Y, Webb HK, Johnson DM, Yu AS, Ulrich RG, Godfrey WR, Miller LL, Spurgeon SE. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014 May 29;123(22):3406-13. doi: 10.1182/blood-2013-11-538546. Epub 2014 Mar 10.
Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. doi: 10.1056/NEJMoa1314583. Epub 2014 Jan 22.
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. doi: 10.1056/NEJMoa1315226. Epub 2014 Jan 22.
Jiang B, Qi J, Song Y, Li Z, Tu M, Ping L, Liu Z, Bao H, Xu Z, Qiu L. Phase 1 clinical trial of the PI3Kdelta inhibitor YY-20394 in patients with B-cell hematological malignancies. J Hematol Oncol. 2021 Aug 23;14(1):130. doi: 10.1186/s13045-021-01140-z.
Related Links
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Other Identifiers
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YY-20394-001
Identifier Type: -
Identifier Source: org_study_id