The Study of ICP-248 in Patients With Mature B-cell Malignancies

Study Overview
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Brief Summary
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This is a Phase I study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ICP-248 in patients with mature B-cell malignancies. This study consists of two parts: Part 1 dose-finding period and Part 2 dose expansion period

Official Title
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A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of ICP-248 in Patients With Mature B-cell Malignancies

Conditions
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Hematological Malignancies

Intervention / Treatment
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* Drug: ICP-248


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 80 years. One of the following histopathologically and/or flow cytometry-confirmed diseases according to the 2016 World Health Organization (WHO) classification criteria for lymphohematopoietic neoplasms or meeting the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria: Histopathologically and/or flow cytometry-confirmed CLL/SLL; Pathologically confirmed MCL; Pathologically confirmed B-NHL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). Relapsed disease or refractory disease For subjects with B-NHL: Patients must have measurable diseasePatients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤ 2 and a life expectancy of ≥ 6 months. Adequate hematologic function. Patients with basically normal coagulation function. Patients with adequate hepatic, renal, pulmonary and cardiac functions. CLL/SLL Patients with an absolute lymphocyte count ≥ 50 x 109/L and any lymph nodes ≥ 5 cm in the long diameter or CLL/SLL or B-NHL patients with any lymph nodes ≥ 10 cm in the long diameter will be enrolled in the study after weighing the risks and benefits with the sponsor's MM. Female patients of childbearing potential must have a negative blood pregnancy test within 7 days prior to the first dose of the investigational product; patients of childbearing potential (males and females) must agree to use a reliable birth control method (hormonal or barrier method or abstinence) with their partners from signing the ICF until 90 days after the last dose. Subjects are able to communicate with the investigator well and to complete the study as specified in the study. Before the trial, the subjects shall understand the nature, significance, possible benefits, inconveniences and potential risks, as well as the study procedures of the trial in detail and voluntarily sign the written Informed Consent Form (ICF). Subjects with CLL/SLL must have an indication for treatment as judged by the investigator. Exclusion Criteria: Prior malignancy (other than the disease under study) within 2 years before study entryKnown Central nervous system involvement by lymphoma/leukemia Underlying medical conditions that, in the investigator's opinion, will render the administration of the investigational product hazardous or obscure the interpretation of the safety or efficacy results. Prior autologous stem cell transplant (unless ≥ 3 months after transplant); or prior chimeric cell therapy (unless ≥ 3 months after cell infusion). Received a BCL-2 inhibitor prior to initial use of the investigational drug and did not achieve disease remission or disease recurrence/progression on treatment; Disease recurrence/progression after stopping or ending BCL-2 inhibitor therapy is acceptable. A history of allogeneic stem cell transplantation. Anti-cancer therapy within 28 days prior to the first dose of the investigational product An interval of less than 5 half-lives from the last dose of a strong CYP3A or CYP2C8 inhibitor or inducer (chemical agent, traditional Chinese medicine and dietary supplement) to the first dose of the investigational product, or a plan to use concurrently medications, dietary supplements or food (e.g., grapefruit or grapefruit juice) with strong CYP3A or CYP2C8 inhibitory or inductive effect during study participation. Patients who have undergone major organ surgery (excluding aspiration biopsy) or significant trauma within 28 days prior to the first dose of the investigational product, or who require elective surgery during the trial. Patients who have received a live attenuated vaccine within 28 days prior to the first dose of the investigational product (except for vaccination to prevent a major public health event). Presence of active infection that currently requires intravenous systemic anti-infective therapy. Patients with active hepatitis B or C virus infection. History of immunodeficiency, including a positive human immunodeficiency virus (HIV) antibody test. History of significant cardiovascular disease Patients with previous or concomitant central nervous system disordersHistory or current evidence of severe interstitial lung disease. ≥ Grade 2 toxicity due to prior anti-cancer therapy at enrollment (except for alopecia, ANC, hemoglobin and PLT). For ANC, hemoglobin and PLT, please follow the inclusion criteria. History of severe bleeding disorder Known alcohol or drug dependence. Presence of mental disorders or poor compliance. Female patients who are pregnant or lactating. Unable to swallow tablets or disease significantly affecting gastrointestinal function. Hypersensitivity to the active substance or excipients of ICP-248 tablets.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ICP-248<br>ICP-248 was divided into 6 dose groups, and each dose group was given progressively | Drug: ICP-248<br>* Eligible patients will receive ICP-248 orally as per the protocol, once daily for every 28 days as one treatment cycle (except for the food effect investigation phase), until progressive disease (PD), intolerable toxicity, withdrawal of consent, loss to follow-up, initiation of other anti-cancer therapy, death, or end of study, whichever occurs first.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and recommended Phase 2 dose | To evaluate the safety and tolerability of ICP-248 monotherapy in the selected B-cell malignancies and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ICP-248 monotherapy | 5 years | 
| To investigate the incidence, nature and severity of adverse events (AE) according to NCI-CTCAE V5.0 or iwCLL2018 evaluation criteria. |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile - Area under curve (AUC0-t) | To evaluate the AUC0-t after single administration of ICP-248 and steady state of ICP-248. | 5 years | 
| Pharmacokinetic (PK) profile - Maximum Concentration (Cmax) | To evaluate the Cmax after single administration of ICP-248 and steady state of ICP-248. | 5 years | 
| Pharmacokinetic (PK) profile - Time to maximum concentration (Tmax) | To evaluate the Tmax after single administration of ICP-248 and steady state of ICP-248. | 5 years | 
| Pharmacokinetic (PK) profile - Apparent clearance (CL/F) | To evaluate the CL/F after single administration of ICP-248 and steady state of ICP-248. | 5 years | 
| Preliminary efficacy - Overall response rate (ORR) | To evaluate the preliminary efficacy of ICP-248 monotherapy in the evaluated disease types as measured by investigator-assessed overall response rate (ORR) | 5 years | 
| Preliminary efficacy - Complete response rate (CRR) | To evaluate the preliminary efficacy of ICP-248 monotherapy in the evaluated disease types as measured by investigator-assessed complete response rate (CRR). | 5 years | 
| Preliminary efficacy - Progression-free survival (PFS) | To evaluate the preliminary efficacy of ICP-248 monotherapy in the evaluated disease types as measured by investigator-assessed progression-free survival (PFS). | 5 years | 
| Preliminary efficacy - Duration of response (DOR) | To evaluate the preliminary efficacy of ICP-248 monotherapy in the evaluated disease types as measured by investigator-assessed duration of response (DOR). | 5 years | 
| Preliminary efficacy - Overall survival (OS) | To evaluate the preliminary efficacy of ICP-248 monotherapy in the evaluated disease types as measured by investigator-assessed overall survival (OS). | 5 years | 
| AUC of ICP-248 under different feeding conditions | To evaluate the AUC of ICP-248 under different feeding conditions. | 5 years | 
| Maximum Concentration (Cmax) of ICP-248 under different feeding conditions | To evaluate the Cmax of ICP-248 under different feeding conditions. | 5 years | 
| Time to maximum concentration (Tmax) of ICP-248 under different feeding conditions | To evaluate the Tmax of ICP-248 under different feeding conditions. | 5 years |