Safety, Tolerability and PK of BTK Inhibitor DTRMWXHS-12 in Patients With B-Cell Lymphomas

Study Overview
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Brief Summary
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The Primary Objective is to evaluate the safety and tolerability of multiple dose oral administration of DTRMWXHS-12 capsule in patients with B-cell lymphoma. The Secondary Objective is to evaluate the pharmacokinetics of multiple dose oral administration of DTRMWXHS-12 capsule in patients with B-cell lymphoma.

Official Title
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Phase Ia Study of the Safety, Tolerability and PK of BTK Inhibitor DTRMWXHS-12 in Patients With B-Cell Lymphoma

Conditions
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Chronic Lymphocytic Leukemia, B-cell Lymphomas

Intervention / Treatment
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* Drug: DTRMWXHS-12


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥18 years, gender is not limited. Patients are voluntary to sign the informed consent form. B-Cell Lymphoma based on WHO classified definition: including chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL); chronic lymphocytic leukemia with 17p-; mantle cell lymphoma (MCL); Waldenstrom's macroglobulinemia(WM); Diffuse large B-cell lymphoma (DLBL or DLBCL) etc. Measurable lesion: non-Hodgkin 's lymphoma requires at least a two-dimensional lesion diameter ≥ 2 cm, chronic lymphocytic leukemia ≥ 5000 leukemia cells / mm3, Waldenstrom's macroglobulinemia IgM ≥ 1000 mg / dL, bone marrow lymph plasma -like cells infiltration, Histopathologically diagnosed as Diffuse Large B- Cell Lymphoma. Investigator judges that the treatment is needed. Patients, who at least failed in lymphoma treatment once and without standard therapeutic options, can't satisfy the requirement or decline treatment or failed in autologous stem cell transplantation for Diffuse Large B- Cell Lymphoma. ECOG (Eastern Cooperative Oncology Group) performance status 0  1 Life expectancy greater than 4 months Ability to swallow capsules Hematologic functions satisfy: Neutrophils ≥1.5×109 / L ( according to the investigators' opinion , if they judge that the patients' neutrophil count lower than this threshold, which caused by chronic lymphocytic leukemia and bone marrow infiltration, those patients are eligible to be included. ), platelet(PLT) ≥75×109/L, HB≥80g/L Renal functions satisfy: Creatinine (Cr) ≤ 1.5 times of upper limit of normal persons; creatinine clearance rate≥50ml/min (estimated by Cockcroft-Gault formula or detected by nuclear medicine scan or 24 hours urine method) Liver functions satisfy: AST and ALT≤2.5 times of normal value, bilirubin ≤1.5 times of normal value Coagulation function: international normalized ratio (INR) and APTT ≤ 1.5 times of normal value; Throughout the course of the study and 90 days of treatment interruption, female of childbearing age and fertile males who must take one of the following effective contraception measures: abstinence, barrier-type dual contraceptive methods, IUDs, administration of hormonal contraception drug. Male subjects are prohibited sperm donation from the start to the end of treatment within 90 days. Exclusion Criteria: Patients with brain metastasis Disease with changes of pathological tissue types (including large cell transformation) Patients who received allogeneic stem cell transplantation within 6 months, or with organized incompatibility reaction (GVHD), requires immunosuppressive therapy Patients who received steroid anti-tumor therapy within 7 days, or receive chemotherapy within 2 weeks, or receive monoclonal antibody therapy within 4 weeks, prior to first administration of DTRMWXHS-12 capsule. Patients received other BTK inhibitor therapy Patients had early received chemotherapy but their toxicity has not been cleared (according to NCI-CTCAE 4.03, unrecovered toxicity grade ≤1) Patients who received Chinese herbal anti-tumor therapy within 1 week before the start of study Patient with a history of other malignant within 2 years before enrollment, except (1) adequately treated in situ cervical cancer;(2) Local basal cell carcinoma or squamous cell carcinoma (3) Local malignant tumor which has been completely treated (by surgery or other means) Patients with uncontrolled systemic infection requiring intravenous anti-infection treatment Patients received major surgery in the past 4 weeks Patients with HIV infection, HBs-Ag positive According to New York Heart Association (NYHA) classification, patients with cardiovascular disease of grade ≥3 Patients with history of Myocardial infarction, acute coronary syndrome (unstable angina), receiving coronary angioplasty and stent implantation within 6 months of study entry Patients applied something which may cause QT prolongation or accompany by torsades healer within 7 days prior to enrollment. Prolonged QTc interval (defined as a QTc> 450 ms) or other significant ECG abnormalities, including second degree atrioventricular block type Ⅱ, third degree atrioventricular block, or bradycardia (heart rate less than 50 beats / min),ECG QTc> 450 milliseconds, the ECG may be submitted to expert for centralized evaluation Subjects, the investigators think whose existing renal disease, neurological / psychiatric disorders, liver or endocrine disorders could affect their participating in the experiment Subjects with poor compliance Subjects are using CYP3A inhibitors (or inducer)

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DTRMWXHS-12<br>DTRMWXHS-12 only: oral capsules (50 mg and 150 mg strengths), successive administration, dose escalation from 50mg to 100, 200, 400, 600, 800mg daily until MTD. During successive administration, orally once a day, 28 days as a cycle. | Drug: DTRMWXHS-12<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | Confirm the safety and tolerability of multiple dose oral administration of DTRMWXHS-12 capsule | Starting from date of first dose up to 30 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of DTRMWXHS-12 | DTRMWXHS-12 Pharmacokinetics | Days 1-28 (first treatment cycle) |