A Phase I Study of LP-108 in Patients With Relapsed or Refractory B-cell Lymphoma

A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the Oral BCL-2 Inhibitor LP-108 in Patients With Relapsed or Refractory B-cell Lymphoma

This study is a multi-center, open-label, single-arm phase I clinical study of LP-108. Patients with relapsed or refractory chronic lymphocytic leukemia (CLL, arm A) and other B cell non-Hodgkin's lymphoma (NHL, Arm B). Each arm has a dose escalation phase (phase Ia) and expansion phase (phase Ib). During the dose escalation phase, the primary objectives are to define dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and to explore a recommended phase II dose. Dose escalation is based on the classic "3 + 3" design, while accelerated titration is applied to the initial lower doses. After the RP2Ds are determined, additional patients will be enrolled in the expansion phase to further evaluation the safety, PK and preliminary efficacy of LP-108, each therapy can enroll 12-20 subjects.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: LP-108 tablet

• Study Type: Interventional
• Enrollment (Anticipated): 74
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • The First Affiliated Hospital of Nanjing Medical University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Per 2017 revised WHO lymphoma classification criteria, subject must have either:

  • (Arm A) Diagnosed with relapsed or refractory CLL and require treatment in the opinion of the Investigator.
  • (Arm B) Diagnosed with relapsed or refractory non-Hodgkin's lymphoma associated with B-cell proliferation (such as SLL \ MCL \ FL \ MZL \ DLBCL \ WM, etc.) in need of treatment.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 1.
• Subject must have adequate bone marrow function independent of growth factor support per local laboratory reference range at Screening.
• Subject must have adequate coagulation, renal, and hepatic function, per local laboratory reference range at Screening.
• All acute toxicity from previous anti-tumor treatment or surgery has been alleviated to NCI CTCAE 5.0 ≤ Grade 1.
• All enrolled patients should take medically approved contraceptives during the entire treatment period and within 90 days after the end of treatment.
• Subjects must be willing to provide valid diagnostic evidence or accept bone marrow biopsy before treatment and accept bone marrow biopsy after treatment start.
• Patients with NHL who have undergone autologous stem cell transplantation must complete the transplantation operation for more than 6 months when enrolled, and have sufficient bone marrow function without relying on growth factor stimulation.
• Volunteer and sign informed consent, willing to follow trial protocol.

Exclusion Criteria:

• According to the 2017 revised WHO Lymphoma Classification Criteria, patients diagnosed with the following diseases: Burkitt lymphoma or Burkitt-like lymphoma, lymphoblastic lymphoma/leukemia, and post-transplant lymphoproliferative disease(PTLD) .
• Previously received other BCL-2 protein family inhibitors.
• CLL subject has undergone an allogeneic or autologous stem cell transplant or NHL subject has undergone an allogeneic stem cell transplant.

• Subjects who have received the following treatments within 4 weeks or 5 half-lives before the first dose of LP-108:

  • Antitumor therapies including myelosuppressive chemotherapy, targeted therapy, biological therapy and / or immunotherapy;
  • Any investigational treatment;
  • Patients who have undergone major surgery, severe trauma or radiotherapy.

• Subjects who have received the following treatments within 2 weeks before the first dose of LP-108:

  • Steroids or traditional herbal medicine for antitumor purposes;
  • Strong and moderate CYP3A4/5 inhibitors and inducers, P-gp inhibitors and CYP2C8 sensitive substrates;
  • All drugs that may cause QTc interval prolongation or torsional tachycardia.
• Have had malignancies other than the indications targeted in this study in the past three years, except for basal cell carcinoma of the skin and cervical carcinoma in situ treated radically.
• Any serious and / or uncontrolled systemic disease.
• Poor cardiovascular function, in line with New York Heart Association (NYHA) cardiac function classification ≥ 2 or QTcF greater than 480ms on ≥ 3 independent ECG.

• Disease states where clinical manifestations may be difficult to control, including

  • HIV, HBV, HCV, syphilis positive or active bacterial and fungal infections;
  • Disease affects the central nervous system with obvious symptoms;
  • Autoimmune hemolytic anemia or Idiopathic thrombocytopenic purpura.
• Any gastrointestinal conditions that may severely affect the study drug absorption or pharmacokinetic parameters.
• Patients who were unable to discontinue taking CYP2C8 substrate repaglinide to control type 2 diabetes during the study.
• Subjects who cannot tolerate urine collection, venipuncture, lymph node biopsy, and bone marrow aspiration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: R/R CLL; Relapsed or Refractory Chronic Lymphocytic Leukemia Patients	Drug: LP-108 tablet; Taken orally within 30 minutes after a meal at the designated dose, once daily.
Experimental: R/R NHL; Relapsed or Refractory B-cell Non-Hodgkin Lymphoma Patients, including SLL, FL, MZL, MCL, DLBCL, WM.	Drug: LP-108 tablet; Taken orally within 30 minutes after a meal at the designated dose, once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of dose limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase two dose (RP2D), and lead-in period regimen	Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, underlying illness, concurrent illness, or concomitant medication, will be considered a DLT. Dose limiting toxicities of tumor lysis syndrome observed during the lead-in period will be attributed to the lead-in period.	Lead-in period (0-4 weeks) plus 3 weeks of study drug administration at the designated cohort dose.
Number of subjects with adverse events and its frequency	Safety Proflie	From first dose of study drug administration until 30 days after study drug discontinue.
Determination of plasma peak concentration (Cmax) of LP-108	Blood and urine samples for pharmacokinetic analysis of LP-108 will be collected at designated time points.	Up to Week 37 for LP-108.
Determination of Area Under the Curve (AUC) of LP-108	Blood and urine samples for pharmacokinetic analysis of LP-108 will be collected at designated time points.	Up to Week 37 for LP-108.
Food Effect - Cmax	Blood samples for food effect pharmacokinetic analysis of LP-108 will be collected at designated time points	Pharmacokinetic (PK) parameter Cmax (maximum plasma concentration of LP-108) between each diet (LP-108 under fasting versus fed conditions)，up to week 8 for LP-108.
Food Effect - AUC	Blood samples for food effect pharmacokinetic analysis of LP-108 will be collected at designated time points	Pharmacokinetic (PK) parameter AUC (area under the curve of LP-108) between each diet (LP-108 under fasting versus fed conditions)，up to week 8 for LP-108.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary efficacy assessment	Tumor response or clinical disease progression	Designated dose starting week for clinical disease progression and tumor response; and every 4-12 weeks thereafter until the date of first documented progression or date of death from any cause, whichever came first,.assessed up to 24 months.
Minimal residual disease (MRD)	MRD assessed in the peripheral blood and/or bone marrow (BM) either by four color flow cytometry or NGS, will be measured in CLL subjects achieving CR/CRi.	At least 2 months after the CR, CRi criteria for tumor response are first met. Measured up to 24 months after the last subject has enrolled in the study.

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Collaborators: Guangzhou Lupeng Pharmaceutical Company LTD.; Newave Pharmaceutical Inc

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2020
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: April 10, 2020
• First Submitted That Met QC Criteria: April 20, 2020
• First Posted (Actual): April 22, 2020

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell
• Other Study ID Numbers: LP-108-I-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No