A Phase I Study of AC0010 in Patients With CLL/ SLL, MCL, DLBCL and Other NHL

Study Overview
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Brief Summary
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This is an open label, dose escalation, phase I study to determine the recommended Phase 2 dose (PR2D) by assessing the DLT, safety and efficacy of AC0010 in patients with B-cell lymphoma.

Detailed Description
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This is an open label, dose escalation, phase I study to determine the PR2D by assessing the DLT, safety and efficacy of AC0010 in patients with B-cell lymphoma. This study includes two parts. During Part 1 Dose Escalation, the 3+3 design will be applied. Dose escalation will begin at dose level 1 = 400 mg. This dose escalation will be followed by an exploratory expansion phase in 3 or 4 groups of 15 41 patients each (CLL group, MCL group, non-germinal center B cell-like DLBCL group, and/or FL/WM(macroglobulinemia) group). The study will further evaluate the safety and efficacy of AC0010 in these patients in each group

Official Title
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A Phase I Study of AC0010 in Patients With Relapsed or Refractory CLL/SLL, MCL, DLBCL and Other Non-Hodgkin B-Cell Lymphoma

Conditions
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B-cell Lymphoma

Intervention / Treatment
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* Drug: AC0010MA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 years and 75 years (included), and patients is over 60 years cannot have more than 3 kinds of heart, lung, liver and kidney complications Histological confirmed CLL/SLL, MCL, non-GCB DLBCL Measurable disease (NHL: At least 1 measurable site of disease [>1.5 centimeter [cm] in the long axis regardless of short axis measurement or >1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions]) In dose escalation phase, other NHL (FL、WM、MZL、BL) patients who are relapsed refractory disease after at least 1 line of previous systemic therapy could be enrolled Could supply stored For Formalin Fixed and Paraffin-Embedded (FFPE) slides or block to the lab for testing or could accept biopsy in the screening. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2 Any of the following hematology values within 14 days prior to inclusion and prior to the first dose of study drug : Absolute neutrophil count (ANC) >= 750 cells/µL(0.75 x 109/L) without growth factors within 7 days prior to the first dose of study drug Spontaneous Platelets count > 50,000 cells/mm3, exclude transfusion dependent thrombocytopenia Adequate heart, liver, lung and renal function: Alkaline phosphatase (ALP) <5* ULN Creatinine determined by serum creatinine levels <=1.5 * ULN or a calculated creatinine clearance of >= 50 mL/min LVEF≥50% as determined by Ultrasonic Cardiogram (UCG) Any prior treatment (chemotherapy, radiotherapy or ) must be completed over 30 days or 5 *half life from the screening; all toxicities related to prior anticancer therapies must be recovered to grade ≤ 1 (CTCAE v 4.03) Patients without central nervous system involvement Life expectancy of more than 6 months Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) or urine pregnancy test negative at Screening Women without pregnant or breastfeeding Exclusion Criteria: Past history of major surgery within 4 weeks before signing the Informed consent form (ICF) Patents with Central nervous system (CNS) lymphoma Patients with prolymphocytic leukemia, patients with Richter's syndrome or suspected with Richter's syndrome Known with primary mediastinal lymphoma • Previous treated with tyrosine kinase inhibitors (TKIs) (including BTK inhibitor) or within 3 months received mono-antibody treatment prior to the first dose of study drug Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the patient has been free of the disease for ≥ 3 years Use of any standard or experimental anti-cancer drug therapy within 30 days prior to the first dose of study drug Autotransplantation within 6 months prior to the first dose of study drug Known received allogeneic stem cell transplantation History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug Requires treatment with anticoagulation with warfarin or equivalent vitamin K antagonists Condition that requires treatment with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification ECG showed abnormal PR, QT and QRS interval (defined as: 12 lead electrocardiogram QT interval corrected Bazett (QTcB) > 430 ms (male) or 450 ms (female), PR> 240 ms, QRS> 110 ms), and electrocardiogram in rhythm, conduction and morphology appeared on the clinical significance of abnormal, such as complete left bundle branch block, myocardial infarction occurred within 6 months; risk factors cause QTc prolongation such as heart failure, arrhythmia, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or first-degree relatives had less than 40 years of history of sudden death or bradycardia (heart rate less than 50 beats per minute) Known HIV, active Hepatitis C Virus (HCV; RNA polymerase chain reaction (PCR)-positive) or active Hepatitis B Virus infection (HBs Ag positive or DNA PCR-positive) or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics All toxicities related to prior anticancer therapies recovered to grade ≤ 1 (exclude any grade alopecia) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times upper limit of normal (ULN) and total bilirubin >1.5xULN Blood urea nitrogen (BUN) or Cr >1.5x upper limits of normal (ULN) Uncontrolled pericardial effusion and pleural effusion History of Parkinson's disease; cerebellar disorders or other motor related diseases; patients with a history of pancreatitis Investigator judgment that patient is unsuitable to participate in study Uncontrolled pleural and pericardial effusion. Pregnant and lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: AC0010MA<br>This is dose escalation study. Patients will receive AC0010MA 200mg bid,300mg bid,400mg bid or 500mg bid by mouth (the dose escalation whether ended depends on DLT and occupancy) everyday until intolerable toxicity or disease progression | Drug: AC0010MA<br>* Participants in the dose escalation cohorts will be treated with AC0010MA every 28 days<br>* Other names: AC0010;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose | Determine the recommended phase II dose (RP2D) of AC0010 in patients with relapsed or refractory CLL/SLL, MCL, DLBCL and other Non-Hodgkin B-Cell lymphoma | On cycle one, up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hours occupancy of AC0010 | AC0010 occupancy of the Bruton's tyrosine kinase (BTK) active site up to 24 hours | 24 hours | 
| Tolerability as measured by adverse events using CTCAE and clinical laboratory parameters | Evaluation of tolerability of AC0010 measured by number, nature and severity of Adverse Events using CTCAE Version 4.03 | Approximately 36 months | 
| Tolerability as measured by number of subjects with dose limiting toxicities | Evaluation of tolerability of AC0010 measured by number of subjects with dose limiting toxicities (DLTs)treatment | on cycle one, up to 28 days | 
| Maximum tolerated dose (MTD) | Maximum Tolerated Dose (MTD) as measured by the number of dose-limiting toxicities in each dose level | on cycle one, up to 28 days | 
| Occupancy of AC0010 after continued treatment | AC0010 occupancy of the BTK active site after continued treatment | On first 4 cycles，up to 4 months | 
| Objective Response Rate (ORR) | Safety and efficacy data will take place at the analysis time point | Approximately 36 months | 
| Cmax | Determine peak plasma concentration (Cmax) after oral administration of AC0010 | Day 1, Day 28, D112 | 
| Tmax | Time to reach maximum observed plasma concentration | 5 min before-dose and 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1, 5 min before-dose and 2, 4, 8, 12 hours post-dose on Day 28, 5 min before-dose on Day 112 | 
| t1/2 | plasma decay half-life | 5 min before-dose and 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1, 5 min before-dose and 2, 4, 8, 12 hours post-dose on Day 28, 5 min before-dose on Day 112 | 
| AUC(0-t) | Area under the curve from time zero to the last quantifiable concentration | 5 min before-dose and 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1, 5 min before-dose and 2, 4, 8, 12 hours post-dose on Day 28, 5 min before-dose on Day 112 | 
| AUC(0-∞) | Area under the curve from time zero to extrapolated infinity | 5 min before-dose and 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1, 5 min before-dose and 2, 4, 8, 12 hours post-dose on Day 28, 5 min before-dose on Day 112 |