Clinical trial NCT03786926: Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Lymphoma
Keywords: CLL
SLL
FL
MZL
LPL
WM
MCL
PTCL
CBCL
Lead sponsor: Hutchmed
Sponsor class: INDUSTRY
First posted: 2018-12-26
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility criteria: 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 PI3Kδ 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.

Primary outcomes:
measure: Number of adverse events as evaluated by the NCI CTCAE v5.0 grade
timeFrame: From first dose to within 30 days after last dose
Secondary outcomes:
measure: maximum plasma concentration (Cmax)
timeFrame: 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)
measure: Area under the concentration-time curve in a selected time interval (AUC0-t)
timeFrame: 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)
measure: Objective response rate (ORR) defined as the proportion of patients who have a CR or PR
timeFrame: from first dose to within 30 days of last dose
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center
state: California
city: Oxnard
country: United States
facility: Ventura County Hematology-Oncology Specialists
state: California
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Westbury
country: United States
facility: Clinical Research Alliance, Inc
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute- Atrium Health
state: North Carolina
city: Dallas
country: United States
facility: Baylor Scott and White Research Institute
state: Texas
city: Houston
country: United States
facility: Renovatio Clinical
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Spokane
country: United States
facility: Medical Oncology Associates, P.S.
state: Washington
city: Helsinki
country: Finland
facility: Helsingin yliopistollinen keskussairaala
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Créteil Cedex
country: France
facility: Hopital Henri Mondor
state: Val De Marne
city: Nantes
country: France
facility: CHU de Nantes - Hotel Dieu
city: Pessac
country: France
facility: CHU de Bordeaux - Hôpital Haut-Lévêque
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Biała Podlaska
country: Poland
facility: KO-MED Centra Kliniczne
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kraków
country: Poland
facility: BioResearch Group Sp. Z. o. o.
city: Toruń
country: Poland
facility: NASZ LEKARZ Osrodek Badan Klinicznych
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego
city: Barcelona
country: Spain
facility: ICO Badalona - Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: ICO l'Hospitalet - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
Study officials:
affiliation: Hutchison Medipharma Limited
name: Vijay Jayaprakash, MD
role: STUDY_DIRECTOR
affiliation: Atrium Health Levine Cancer Institute
name: Nilanjan Ghosh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory Winship Cancer Institute
name: Jonathan B Cohen, MD
role: PRINCIPAL_INVESTIGATOR
References: