A Study of Hutchison MediPharma Limited(HMPL)-523 in Patients With Relapsed or Refractory Mature B-cell Neoplasms

A Phase I, Open-label, Dose-escalation Study of the Safety and Pharmacokinetics of HMPL-523 in Patients With Relapsed or Refractory Mature B-cell Neoplasms

A Phase I, Open-label, Dose-escalation Study of the Safety and Pharmacokinetics of HMPL-523 in Patients With Relapsed or Refractory Mature B-cell Neoplasms

Study Overview

• Status: Unknown
• Conditions: Mature B-cell Neoplasms
• Intervention / Treatment: Drug: HMPL-523

Detailed Description

There are two stages in this study: a dose-escalation stage (stage 1) and a dose-expansion stage (stage 2).

Dose-escalation stage (stage 1):

The conventional 3+3 design (3 patients per dose cohort, with the potential to add additional 3 patients to the same cohort to further evaluate toxicity) will be applied for dose escalation and maximum tolerated dosage determination. Approximately 27 to 42 dose limited toxicities evaluable patients will be enrolled. The actual number of patients depends on the dose limited toxicities situation as well as the maximum tolerated dosage reached at this stage.

Dosing will begin at 200mg once daily. A cycle of study treatment will be defined as 28 days of continuous dosing.

Dose-expansion stage (stage 2):

This phase is to further evaluate the safety, the pharmacokinetics and anti-tumor activity of HMPL-523 at recommended phase 2 dosage in approximately 190 patients with relapsed or refractory Hematologic Malignancies.

In this stage, approximately 190 patients with Mature B-cell Neoplasms will be enrolled with recommended phase 2 dosage 600milligram(mg) one a day(QD) as starting dosing. The tumor types of the expansion stage are restricted to Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), Mantle cell lymphoma (MCL), Follicular Lymphoma (FL), Diffuse large B-cell lymphoma (DLBCL), Marginal zone lymphoma (MZL)and Waldenstrom's macroglobulinemia (WM)/Lymphoplasmacytic lymphoma(LPL) Subjects will receive HMPL-523 with every 28-day treatment cycle until disease progression, death, or intolerable toxicity, whichever comes first.

• Study Type: Interventional
• Enrollment (Anticipated): 217
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 200032
    • Recruiting
    • Fudan University Shanghai Cancer Hospital
    • Contact: Junning Cao; Email: cao_junning@126.com
  • Beijing
    • Beijing, Beijing, China
      • Recruiting
      • BeijingCancer Hospital
      • Contact: Jun Zhu; Email: zhujun@csco.org.cn
      • Principal Investigator: Jun Zhu, MD.PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed Informed Consent Form
2. Age >=18 years
3. Histologically relapsed or refractory mature B-cell Neoplasms, have failed at least one prior therapy or patients who are unable to tolerate standard therapy or no curative therapy or therapy of higher priority exists
4. Eastern Cooperative Oncology Group（ECOG） performance status of 0 or 1
5. Expected survival of more than 24 weeks as determined by the investigator
6. In expansion stage, Subjects should have at least one dual diameter measurable lesion expect for subject with CLL or subject with LPL/WM with abonormal immunoglobulin

Exclusion Criteria:

1. Patients with primary central nervous system(CNS) lymphoma

2. Any of the following laboratory abnormalities:

   • Absolute neutrophil count<1.5×109/L
   • Hemoglobin <80g/L
   • Platelet<75 ×109 /L

3. Inadequate organ function, defined by the following:

   • Total bilirubin >1.5the ULN with the following exception:

     • Patients with known Gilbert disease who have serum bilirubin level ≤3 the upper limit of normal(ULN) and normal Aspartate aminotransferase(AST)/Alanine aminotransferase(ALT) may be enrolled.
4. AST and/or ALT > 2.5 the ULN with the following exception:Patients with documented disease infiltration of the liver may have AST and/or ALT levels ≤ 5 the ULN.
5. Serum amylase or lipase > the ULN
6. Serum creatinine > 1.5 the ULN or estimated creatinine clearance < 50 mL/min
7. International normalized ratio (INR)>1.5 the ULN or activated partial thromboplastin time (aPTT)>1.5 the ULN
8. Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)
9. Pregnant (positive pregnancy test) or lactating women
10. New York Heart Association (NYHA) Class II or greater congestive heart failure
11. Congenital long QT syndrome or corrected QT interval (QTc) > 480 msec
12. Currently use medication known to cause QT prolongation.
13. Subjects with presence of clinically detectable second primary malignant tumors at enrollment, or other malignant tumors within the last 2 years (with the exception of radically treated basal cell or squamous cell carcinoma of the skin, in situ cervix, or in situ breast cancer).
14. Any anti-cancer therapy, including chemotherapy, hormonal therapy, biologic therapy, or radiotherapy within 3 weeks prior to initiation of study treatment
15. Herbal therapy ≤1 week prior to initiation of study treatment
16. Prior treatment with any spleen tyrosine kinase (SYK) inhibitors (Fostamatinib)
17. Prior allogeneic stem cell transplant within 6 months prior to initiation of study treatment or with any evidence of active graft versus host disease or requirement for immunosuppressants within 28 days prior to initiation of study treatment
18. Clinically significant active infection (pneumonia)
19. Major surgical procedure within 4 weeks prior to initiation of study treatment
20. History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment
21. Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease
22. Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤1, except for alopecia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HMPL-523; Oral administration, at dose of 200, 400, 600 and 800 mg once daily;at dose of 200,300, 400mg twice daily at Dose-escalation stage; At Dose-expansion stage, if patients dosing at 600mgQD.	Drug: HMPL-523; Oral administration, once daily; Other Names: HMPL-523 Acetate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limited toxicities evaluated with NCI CTCAE v4.03	Incidence of dose limited toxicities and associated dose of HMPL-523	within 28 days after the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	the proportion of subjects who have a Complete Response or Partial Response	within 30 days after the last dose
Maximum plasma concentration calculated with Blood samples	Blood samples will be taken to measure the levels of study drug	within 29 days after the first dose
Time to reach maximum concentration calculated with Blood samples	Blood samples will be taken to measure the levels of study drug	within 29 days after the first dose
Adverse events evaluated by NCI CTCAE v4.03	Incidence of adverse events and associated dose of HMPL-523	from the first dose to within 30 days after the last dose

Collaborators and Investigators

• Sponsor: Hutchison Medipharma Limited
• Investigators: Study Chair: Chen Yang, M.D., Hutchison Medipharma Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2016
• Primary Completion (Anticipated): February 1, 2021
• Study Completion (Anticipated): February 1, 2021

Study Registration Dates

• First Submitted: August 3, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (Estimate): August 5, 2016

Study Record Updates

• Last Update Posted (Actual): February 27, 2020
• Last Update Submitted That Met QC Criteria: February 25, 2020
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms; Lymphoma, B-Cell
• Other Study ID Numbers: 2015-523-00CH1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO