A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of ICP-248 as Monotherapy or in Combination Therapy in Patients With Mature B-cell Malignancies
Overview
- Phase
- Phase 1
- Intervention
- ICP-248
- Conditions
- Hematological Malignancies
- Sponsor
- Beijing InnoCare Pharma Tech Co., Ltd.
- Enrollment
- 191
- Locations
- 22
- Primary Endpoint
- Maximum tolerated dose and recommended Phase 2 dose
- Status
- Recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of ICP-248 as Monotherapy or in Combination Therapy in Patients with Mature B-cell Malignancies.This study consists of two parts: Part 1 dose-finding period and Part 2 dose expansion period.
Investigators
Eligibility Criteria
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.The last ICP- 248 dose or within one month after the last dose of Orelabrutinib Or within 12 months after the last dose of Rituximab (whichever is longer).
- •Subjects are able to communicate with the investigator well and to complete the study as specified in the study.
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 14 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 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 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).
Arms & Interventions
Dose-Escalation Cohort - R/R CLL/SLL and R/R MCL
ICP-248 was divided into 6 dose groups, and each dose group was given progressively
Intervention: ICP-248
Dose-Expansion Cohort A/B/C/D/E/F (R/R CLL/SLL、R/R MCL、R/R B-NHL)
Participants will receive ICP-248 daily with a weekly ramp-up schedule from Cycle 1 day 1.
Intervention: ICP-248
Dose-Expansion Cohort G(R/R MCL)
Participants will receive ICP-248 daily with a ramp-up phase, and will receive Orelabrutinib 150 mg daily, 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.
Intervention: ICP-248+Orelabrutinib
Dose-Expansion Cohort H(R/R MZL)
Participants will receive ICP-248 daily with a weekly ramp-up schedule and Orelabrutinib 150 mg daily from Cycle 1 day 1, 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.
Intervention: ICP-248+Orelabrutinib
Dose-Expansion Cohort I(R/R CLL/SLL)
Participants will receive ICP-248 daily with a weekly ramp-up schedule from Cycle 1 day 1, and will receive 375 mg/m2 Rituximab on day 1 of each cycle from C1 to C6,or 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.
Intervention: ICP-248 +Rituximab
Dose-Expansion Cohort J(R/R CLL/SLL)
Participants will receive Orelabrutinib 150 mg daily from cycle 1 day 1, and will receive ICP-248 daily with a daily ramp-up schedule from Cycle 3 day 1, 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.
Intervention: ICP-248+Orelabrutinib
Dose-Expansion Cohort K(MCL)
Participants will receive Orelabrutinib 150 mg daily from cycle 1 day 1, and Rituximab 375 mg per square meter was infused intravenously on day 1 of each cycle from C1-6 and on day 1 of every two cycles from C7D1 onwards, and ICP-248 daily with a weekly ramp-up schedule from cycle 3 day 1. The treatment will continue up to a maximum of 24 cycles, or 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.
Intervention: ICP-248+Orelabrutinib+Rituximab
Outcomes
Primary Outcomes
Maximum tolerated dose and recommended Phase 2 dose
Time Frame: 5 years
To evaluate the safety and tolerability of ICP-248 monotherapy or combination with Orelabrutinib in the selected B-cell malignancies and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ICP-248
To investigate the incidence, nature and severity of adverse events (AE) according to NCI-CTCAE V5.0 or iwCLL2018 evaluation criteria.
Time Frame: 5 years
To evaluate the investigator-assessed overall response rate (ORR) of ICP-248 monotherapy or combination therapy at the recommended phase II dose (RP2D) .
Time Frame: 5 years
Secondary Outcomes
- Pharmacokinetic (PK) profile - Area under curve (AUC0-t)(5 years)
- Pharmacokinetic (PK) profile - Maximum Concentration (Cmax)(5 years)
- Pharmacokinetic (PK) profile - Time to maximum concentration (Tmax)(5 years)
- Pharmacokinetic (PK) profile - Apparent clearance (CL/F)(5 years)
- Preliminary efficacy - Complete response rate (CRR)(5 years)
- Preliminary efficacy - Progression-free survival (PFS)(5 years)
- Preliminary efficacy - Duration of response (DOR)(5 years)
- Preliminary efficacy - Overall survival (OS)(5 years)
- AUC of ICP-248 under different feeding conditions(5 years)
- Maximum Concentration (Cmax) of ICP-248 under different feeding conditions(5 years)
- Time to maximum concentration (Tmax) of ICP-248 under different feeding conditions(5 years)