Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas

Lymphoma Clinical Trial

Official title:

A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMPL-689 in Patients With Relapsed or Refractory Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03786926
• Other study ID #: 2018-689-00US1
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: August 26, 2019
• Est. completion date: December 31, 2024

Study information

• Verified date: February 2024
• Source: Hutchmed
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability and PK of HMPL-689 in patients with relapsed or refractory lymphomas

Description:

This is a Phase 1, open-label, multicenter study of HMPL-689 administered orally to patients with relapsed or refractory lymphoma.

HMPL-689 is a selective and potent small molecule inhibitor targeting the isoform phosphoinositide 3'-kinase delta (PI3Kδ), a key component in the B-cell receptor signaling pathway

This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2).

Dose Escalation Stage (Stage 1):

This stage will end when any of the following criteria is met:

• The dose level 1 demonstrates an excessive toxicity, ie, 3 dose limiting toxicities (DLTs) are observed out of the first 3 patients at dose level 1.

• The maximum sample size is reached.

• The MTD and/or RP2D is confirmed.

Dose Expansion Stage (Stage 2):

To further characterize the safety and explore the preliminary anti-tumor activity of HMPL-689 at RP2D, patients with B cell lymphoma will be enrolled in the dose expansion stage.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 53
• Est. completion date: December 31, 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. (ECOG) performance status of 0 or 1;

2. Histologically confirmed lymphoma (tumor types are restricted to CLL/SLL, FL (grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL);

3. Patients with relapsed or refractory NHL for whom:

• Standard of care treatment options no longer exist (Stage 1 only);

• Standard of care treatment options no longer exist with the exception of PI3K-delta inhibitors (Stage 2 only);

4. Expected survival of more than 24 weeks.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Primary central nervous system (CNS) lymphoma;

2. Any of the following laboratory abnormalities Absolute neutrophil count; <1.0×10^9/L, Hemoglobin <80 g/L Platelets <50 ×10^9/L

3. Inadequate organ function, defined by the following:

• Total bilirubin =1.5 times the upper limit of normal (× ULN);

• AST or ALT > 2.5 × ULN;

• Estimated creatinine clearance (CrCl) per Cockcroft-Gault;

• Dose Escalation stage of trial (Stage 1) - CrCl < 40 mL/min;

• Dose Expansion stage of trial (Stage 2) - CrCl <30 mL/min;

4. International normalized ratio (INR) > 1.5 × ULN, activated partial thromboplastin time (aPTT) > 1.5 × ULN;

5. Serum amylase or lipase > ULN at screening or known medical history of serum amylase or lipase > ULN;

6. Patients with presence of second primary malignant tumors within the last 2 years;

7. Clinically significant history of liver disease;

8. Prior treatment with any PI3Kd inhibitors;

9. Any prior use of the following: cancer therapy within 3 weeks of study treatment, GCSF within 7 days of screening, steroid therapy or targeted anti-neoplastic intent within 7 days of treatment, any use of strong CYP3A4 inducers within 2 weeks prior to initiation of study treatment, prior autologous transplant within 6 months of study treatment, prior allogenic stem cell transplant within 6 months of study treatment;

10. Clinically significant active infection or interstitial lung diseases (including drug induced pneumonitis);

11. Major surgical procedure within 4 weeks prior to initiation of study treatment;

12. Adverse events from prior anti-neoplastic therapy that have not resolved to Grade less than or equal to 1, except for alopecia;

13. New York Heart Association (NYHA) Class II or greater congestive heart failure;

14. Congenital long QT syndrome or QTc >470 msec;

15. Currently use medication known to cause QT prolongation or torsades de pointes;

16. History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment;

17. History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment;

18. Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease;

19. History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis);

20. Patients with ongoing chronic gastrointestinal diseases;

21. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.

Related Conditions & MeSH terms

• Lymphoma

Intervention

Drug:
• HMPL-689
HMPL-689 is a PI3Kd inhibitor

Locations

Country	Name	City	State
Finland	Helsingin yliopistollinen keskussairaala	Helsinki
Finland	Tampereen yliopistollinen sairaala	Tampere
France	Hopital Henri Mondor	Créteil Cedex	Val De Marne
France	CHU de Nantes - Hotel Dieu	Nantes
France	CHU de Bordeaux - Hôpital Haut-Lévêque	Pessac
Italy	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS	Bologna
Italy	Ospedale San Raffaele	Milan
Poland	KO-MED Centra Kliniczne	Biala Podlaska
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	BioResearch Group Sp. Z. o. o.	Kraków
Poland	NASZ LEKARZ Osrodek Badan Klinicznych	Torun
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego	Wroclaw
Spain	ICO Badalona - Hospital Universitari Germans Trias i Pujol	Barcelona
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	Barcelona
Spain	Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Seville
Spain	Hospital Universitario Virgen Macarena	Seville
United States	Innovative Clinical Research Institute	Anaheim	California
United States	Pacific Cancer Medical Center	Anaheim	California
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Levine Cancer Institute- Atrium Health	Charlotte	North Carolina
United States	Baylor Scott and White Research Institute	Dallas	Texas
United States	Renovatio Clinical	Houston	Texas
United States	Ventura County Hematology-Oncology Specialists	Oxnard	California
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Medical Oncology Associates, P.S.	Spokane	Washington
United States	Clinical Research Alliance, Inc	Westbury	New York

Sponsors (1)

Lead Sponsor	Collaborator
Hutchmed

Countries where clinical trial is conducted

United States,  Finland,  France,  Italy,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of adverse events as evaluated by the NCI CTCAE v5.0 grade	The safety and tolerability of HMPL-689 dose will be evaluated based on adverse events data	From first dose to within 30 days after last dose
Secondary	maximum plasma concentration (Cmax)	To characterize the pharmacokinetic (PK) properties of HMPL-689 in patients with relapsed or refractory lymphoma	from cycle 1 day 1 30 min pre-dose until cycle 2 day 1 30 min pre dose (escalation) from cycle 1 day 1 30 min pre-dose to Cycle 5 day 1 pre-dose 30 min (expansion) (cycle is 28 days)
Secondary	Area under the concentration-time curve in a selected time interval (AUC0-t)	To characterize the pharmacokinetic (PK) properties of HMPL-689 in patients with relapsed or refractory lymphoma	from cycle 1 day 1 30 min pre-dose until cycle 2 day 1 30 min pre dose (escalation) from cycle 1 day 1 30 min pre-dose to Cycle 5 day 1 pre-dose 30 min (expansion) (cycle is 28 days)
Secondary	Objective response rate (ORR) defined as the proportion of patients who have a CR or PR	To evaluate the anti-tumor activity of HMPL-689 in patients with relapsed or refractory lymphoma according to: (1) Chronic Lymphocytic Leukemia (CLL) - modified International Workshop on CLL guidelines, (2) Waldenstrom's Macroglobulinemia (WM) - consensus of international workshops on WM, (3) Lymphomas other than CLL or WM: Lugano Response Criteria for Hodgkin and Non-Hodgkin's Lymphoma	from first dose to within 30 days of last dose