A Phase I Study of YY-20394 in Patients With B Cell Hematologic Malignancies

Protocol YY-20394-001 is a phase I open-label, first in human, dose escalation study to assess the tolerability, pharmacokinetics (PK) and efficacy of YY-20394 in patients with relapse or refractory B cell malignant hematological tumor.

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 ≥ 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.

Eligibility Criteria:
Inclusion Criteria:

1. Males and/or females over age 18
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:

1. Previously treated with PI3Kδ inhibitors and cause disease progression.
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.