Evaluate the Safety, Tolerability, and Efficacy of ICP-490 in Patients With Relapsed and/or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This is a multi-center, non-randomized and open-label phase I/IIa clinical study to evaluate the safety, tolerability, and efficacy of ICP-490 in patients with relapsed and/or refractory multiple myeloma.

Official Title
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A Multi-center, Non-randomized, and Open-label Phase I/IIa Clinical Study to Evaluate the Safety, Tolerability, and Efficacy of ICP-490 in Patients With Relapsed and/or Refractory Multiple Myeloma

Conditions
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Relapsed and/or Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: ICP-490


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years old. Diagnosed as relapsed and/or refractory multiple myeloma .The patient must have measurable diseases.Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-2. Patients must have adequate organ function. Expected survival time ≥ 6 months. All toxicities caused by prior anticancer therapy must have recovered to Grade ≤ 1 (based on CTCAE v5.0) except alopecia and fatigue. Female patients of childbearing potential should have a negative blood pregnancy test result within 48 h prior to the first dose of investigational drug. Exclusion Criteria: Known active central nervous system (CNS) involvement or history of the disease, or clinical signs of multiple myeloma meningeal/spinal meningeal involvement. Patients with solitary plasmacytoma; plasma cell leukemia (PCL) (active PCL or history of PCL); Waldenström's macroglobulinemia; POEMS syndrome or symptomatic amyloidosis. Prior active or history of malignancies other than MM, occurring within 5 years prior to the first dose of investigational drug, with the exception of radically treated local curable cancers. Uncontrolled or severe cardiovascular disorders. Presence or history of clinically significant CNS diseases or pathological changes.Any active infection within 14 days prior to the first dose of investigational drug. Patients with active HBV,HCV,HIV infection. Subjects with clinically significant gastrointestinal anomalies that may affect drug intake, transport, or absorption. Having undergone major surgery within 28 days prior to the first dose of investigational drug, or minor surgery within 2 weeks prior to the first dose. Any severe or uncontrolled systemic disease evaluated by investigatorthat may increase the risk associated with study participation and drug administration or affect the patient's ability to receive the investigational drug. Patients who have received any other systemic treatment, anti-tumor traditional Chinese (herbal) medicine therapy , and any other investigational drug therapy for MM within 28 days or 5 half-lives of the drugs (whichever is shorter) prior to the first dose of investigational drug. Patients who have received systemic treatment with corticosteroids (dose equivalent to > 10 mg/day prednisone) or other immunosuppressive drugs within 14 days prior to the first dose of investigational drug. Subjects are allowed to use topical, ocular, intra-articular, intranasal, and inhaledcorticosteroid ; short-term use (≤ 7 days) of corticosteroid for prophylaxis (e.g., contrast agent allergy) or for the treatment of non-autoimmune diseases (e.g., delayed hypersensitivity reaction caused by contact allergens) is permitted. Patients who have received medications or foods with strong inhibitory or inductive effects on cytochrome P450 CYP3A, and proton pump inhibitorswithin 2 weeks prior to the first dose of investigational drug, or are planning to receive them during the study. Patients with a history of severe allergic reactions to IMIDs , or dexamethasone, or to any component contained in ICP-490 or dexamethasone formulation (CTCAE V5.0 Grade > 3).

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ICP-490<br>ICP-490 is administered continuously on Days 1-21, QD in every 28-day cycle. Patients who develop progressive disease (PD) at any timepoint during ICP-490 treatment, or who do not respond after completing 4 treatment cycles, dexamethasone can be added to the current ICP-490 dose level. | Drug: ICP-490<br>* The initial dose of ICP-490 is 0.1 mg, five dose groups are planned for the dose exploration (0.1 mg to 1.5 mg).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I : Incidence, type, and severity of adverse events (AEs) as judged according to NCI-CTCAE V5.0 | AE refers to any adverse event occurring in subjects during clinical research period. The incidence and type of AEs will be evaluated and the severity will be judged according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version5.0. | Through study completion, an average of 3 years | 
| Phase I : Incidence, type, and severity of dose-limiting toxicities (DLTs) | The dose-limiting toxicity (DLT) assessed in the phase I dose exploration study is defined as AEs related to study treatment that meet the following criteria (according to the NCI CTCAE v5.0 criteria) and occur in Cycle 1. | Through study completion, an average of 3 years | 
| Phase I : RP2Ds and/or MTDs | Phase I is the dose exploration study of ICP-490 to preliminarily determine RP2Ds (probably more than one) and MTD (if applicable). MTD: The dose level corresponding to the dose group whose posterior probability of DLT incidence estimated by PAVA (pool adjacent violators algorithm) is closest to the target toxicity probability (25%). | Through study completion, an average of 3 years | 
| Phase II : ORR (defined as sCR + CR + VGPR + PR) assessed according to IMWG criteria. | Disease response will be assessed according to the 2016 IMWG response criteria. | Through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) | Maximum concentration (Cmax) will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| Time to maximum concentration (Tmax) | Time to maximum concentration (Tmax) will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| Half-life (T1/2) | Half-life (T1/2) will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| Area under the concentration-time curve (AUC0-∞ and AUC0-t) | Area under the concentration-time curve (AUC0-∞ and AUC0-t) will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| Apparent clearance (CL/F) | Apparent clearance (CL/F) will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| Apparent volume of distribution during terminal phase (Vz/F) | Apparent volume of distribution during terminal phase (Vz/F) will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| Steady-state PK parameters | Steady-state PK parameters will be calculated through multiple plasma concentrations drawn from the patients after administration. | Through study completion, an average of 3 years | 
| The overall response rate (ORR) assessed according to the International Myeloma Working Group (IMWG) criteria (ORR, defined as stringent complete response (sCR) + complete response (CR) + very good partial response (VGPR) + partial response (PR)) | Disease response will be assessed according to the 2016 IMWG response criteria. | Through study completion, an average of 3 years | 
| Phase I & IIa : Complete response rate (CRR, defined as sCR + CR) assessed according to IMWG criteria | Disease response will be assessed according to the 2016 IMWG response criteria. | Through study completion, an average of 3 years | 
| Phase I & IIa : Very good or better partial response rate assessed according to IMWG criteria (≥ VGPR rate, defined as VGPR + sCR + CR) | Disease response will be assessed according to the 2016 IMWG response criteria. | Through study completion, an average of 3 years | 
| Phase I & IIa : Time to response (TTR) assessed according to IMWG criteria | Disease response will be assessed according to the 2016 IMWG response criteria | Through study completion, an average of 3 years | 
| Phase I & IIa : Duration of response (DOR) assessed according to IMWG criteria | Disease response will be assessed according to the 2016 IMWG response criteria | Through study completion, an average of 3 years | 
| Phase I & IIa : Progression-free survival (PFS) assessed according to IMWG criteria | Disease response will be assessed according to the 2016 IMWG response criteria | Through study completion, an average of 3 years | 
| Phase I & IIa : Overall survival (OS) | The follow-up visits should be carried out every 12 weeks after the last dose via telephone or other methods to obtain the survival status information of patients. | Through study completion, an average of 3 years |