A Study to Evaluate ICP-022 in Patients With R/R Mantle Cell Lymphoma (MCL)

Study Overview
=================
Brief Summary
-----------------
The phase I/II clinical study is to investigate the safety, tolerability and pharmacokinetics/ pharmacodynamics of ICP-022.

Detailed Description
-----------------
Part I: PK/PD and safety evaluation -Two regimens of ICP-022 (High dose QD and low dose BID) were designed for assessment of safety, as well as PK/PD profiles. The recommended dose of phase II clinical study will be determined according to the Part I results. Part II: Dose expansion -Anti-tumor effects of ICP-022 in Chinese patients with R/R MCL will be evaluated in approximately 80 subjects. The recommended Phase 2 dose will be used in the Part II.

Official Title
-----------------
A Multicenter, Open-label Study to Evaluate the Safety and Efficacy of ICP-022 in Patients With Relapsed/Refractory Mantle Cell Lymphoma (MCL)

Conditions
-----------------
Mantle Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: ICP-022


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between 18 and 75 years old Histologically confirmed mantle cell lymphoma (MCL), with either t(11;14) by cytogenetics and/or cyclin D1 overexpression by immunohistochemistry (IHC) Subjects with refractory or relapsed mantle cell lymphoma who has received at least 1 but no more than 4 prior therapies for MCL At least one measurable tumor of greater than 1.5 centimeter in long axis by contrast-enhanced CT/MRI ECOG performance status of 0-2 Documented failure to achieve at least partial response (PR) or documented disease progression after response to, the most recent treatment regimen. Subjects who meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥ 1.5×109/L Platelet count ≥ 75×109/L, independent of growth factor support within 7 days of the first dose with study drug, Hemoglobin ≥ 80 g/L; ANC ≥ 1.0×109/L, Platelet count ≥ 50×109/L if bone marrow involvement Total bilirubin ≤ 2× ULN; AST or ALT ≤ 2.5 ULN; Creatinine clearance ≥ 30ml/min; Amylase ≤ ULN and Lipase ≤ ULN International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (APTT) ≤ 1.5 ULN Life expectancy ≥ 4 months Able to provide signed written informed consent Exclusion Criteria: History of other active malignancies within 5 years of study entry, unless cured without evidence of relapse or metastasis Current or history of lymphoma involved central nervous system Prior corticosteroids (at dosages equivalent to prednisone > 20 mg/day) given with anti-neoplastic intent within 7 days, prior chemotherapy, targeted therapy, radiation therapy, or antibody based therapies or anti-cancer TCM within 4 weeks of the start of study drug. Non-hematological toxicity must recover to ≤ Grade 1 from prior anti-cancer therapy Current clinically significant cardiovascular disease including: Any class 3 or 4 cardiac disease such as arrhythmia, congestive heart failure or myocardial infarction defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) < 50% Primary cardiomyopathy Clinical significant QTc prolong history or QTc>470ms (female) QTc>450ms (male) Uncontrolled hypertension Known active bleeding within 2 months of screening or currently taking anticoagulant/antiplatelet drugs Urine protein ≥ 2+ and quantitation ≥ 2g/24hours History of deep vein thrombosis or pulmonary embolism Disease significantly affecting gastrointestinal function such as dysphagia, chronic diarrhea, intestinal obstruction, or resection of the stomach Allogeneic stem cell transplant within 6 months prior to first dose of study drug or related active infection Major surgery within 6 weeks of screening, except for diagnostic test or vascular access setup Known active infection with HBV, HCV or HIV or any uncontrolled active systemic infection Any history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe lung function impairment Prior exposure to a BTK inhibitor，BCR pathway ingibitor(such as PI3K, SYK) or BCL-2 kinase inhibitor Suitable and ready for allogeneic stem cell transplant Inability to comply with study procedures Drug abuser or alcoholics Lactating or pregnant women, or women who will not use contraception during the study and for 180 days after the last dose of study drug if sexually active and able to bear children Requires treatment with moderate or strong cytochrome P450 family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose of ICP-022<br>Two regimens of ICP-022 (High dose QD and low dose BID) are designed for study Part I to determine RP2D which will be used in Part II to further evaluate the preliminary anti-tumor effects of ICP-022 in Chinese subjects with R/R MCL. | Drug: ICP-022<br>* The drug product is a white, round, uncoated tablet.<br>|
| Experimental: Low Dose of ICP-022<br>Two regimens of ICP-022 (High dose QD and low dose BID) are designed for study Part I to determine RP2D which will be used in Part II to further evaluate the preliminary anti-tumor effects of ICP-022 in Chinese subjects with R/R MCL. | Drug: ICP-022<br>* The drug product is a white, round, uncoated tablet.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate (ORR) | The efficacy measured by overall response rate (ORR) in Part II according to the 2014 International Working Group NHL | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events and serious adverse events according to NCI-CTCAE 4.03 grading criteria in Part I | The safety of ICP-022 measured by the occurrence of adverse events and serious adverse events according to NCI-CTCAE 4.03 grading criteria in Part I | Up to 3 years | 
| time to progression (TTP) | The efficacy measured by time to progression (TTP) in Part II | Up to 3 years | 
| progression free survival (PFS) | The efficacy measured by progression free survival (PFS) in Part II | Up to 3 years | 
| overall survival (OS) | The efficacy measured by overall survival (OS) in Part II | Up to 3 years | 
| Area under the concentration time curve up to the time t (AUC(0-t)) | Area under the concentration time curve up to the time t (AUC(0-t)) of ICP-022 will be measured and calculated with noncompartmental analysis using WinNonlin. | up to 4 weeks | 
| The percent of target occupancy | PBMC from individual subject before and after dosing will be collected and the target occupancy will be determined by ELISA. The percent of target occupancy will be compared descriptively. | up to 4 weeks | 
| Maximum plasma drug concentrations (Cmax) | Individual plasma concentrations of ICP-022 will be measured and Cmax will be calculated with noncompartmental analysis using WinNonlin. | up to 4 weeks | 
| Time of maximum plasma drug concentrations (Tmax) | Time of maximum plasma drug concentrations (Tmax) of ICP-022 will be recorded. | up to 4 weeks | 
| Apparent half-life for designated elimination phases (t½) | Apparent half-life for designated elimination phases (t½) of ICP-022 will be measured and calculated with noncompartmental analysis using WinNonlin. | up to 4 weeks | 
| Area under the concentration time curve up to the last data point above LOQ (AUC(last)) | Area under the concentration time curve up to the last data point above LOQ (AUC(last)) of ICP-022 will be measured and calculated with noncompartmental analysis using WinNonlin. | up to 4 weeks |