This is a Phase 1 Study of MH048 in Patients With Selected Relapsed/Refractory B-cell Malignancies

Study Overview
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Brief Summary
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This is a Phase 1 study of MH048 in patients with selected Relapsed/Refractory B-cell Malignancies.

Detailed Description
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This is an open-label, multi-center Phase 1 study of MH048 in patients with selected Relapsed/Refractory B-cell Malignancies. This study includes 2 parts: Part A is the dose escalation part of the study, and Part B is the dose expansion part of the study. In Part A, patients were enrolled using accelerated titration design for the first three single patient cohorts and 3+3 dose escalation design for the rest cohorts. The starting dose of MH048 in soft gel capsule form was 5 mg/day QD. Cycle length will be 28 days. In Part B, the dose and lymphoma subtypes for expansion phase will depend on the results from Part A.

Official Title
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A Phase 1, Multicenter, Open-Label, Dose Escalation and Dose Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Antitumor Activity of MH048 in Subjects With Selected Relapsed/Refractory B-cell Malignancies

Conditions
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Relapsed/Refractory B-cell Malignancies

Intervention / Treatment
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* Drug: MH048


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects ≥18 years of age; Willing and able to understand and sign an informed consent form and to comply with all aspects of the protocol; Life expectancy of ≥12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; Histologically confirmed B-cell Malignancies who have relapsed or are refractory to standard of care therapies, and have received ≥1 prior lines of therapy: Part A: Subjects with B-cell Malignancies (regardless of subtype); Part B: Subjects With Selected Relapsed/Refractory B-cell Malignancies based on data from Part A; There must be radiographically measurable disease for effects assess at dose expansion cohort; Adequate organ function, as specified below: Hematologic: Platelet count >65 × 10^9/L (may be posttransfusion, must one week before the first dose of starting study treatment); Hemoglobin (Hgb) ≥ 80 g/L; international normalized ratio (INR) or plasma prothrombin time (PT) ≤1.5 × ULN; absolute neutrophil count >1.0 × 10^9/L (growth factor use is allowed to bring pre-treatment neutrophils to >1.0 × 10^9 cells/L if bone marrow infiltration is involved, provided this is not within 7 days of starting study treatment); Hepatic: Total bilirubin <1.5 × upper limit normal (ULN), Total bilirubin <3 × ULN for Gilbert Syndrome; Aspartate aminotransferase (AST) and Alanine transaminase (ALT) ≤2.5 × ULN; Renal: Creatinine clearance ≥60 mL/min (as estimated by the Cockcroft-Gault equation ); Willing to have bone marrow biopsy/aspirate for baseline disease assessment and assessment of response to treatment; Willingness of men and women of reproductive potential to observe conventional and highly effective birth control from the beginning of the study screening until 6 months after receiving the last treatment of investigational product. A fertile woman must be confirmed by a positive serum beta-human chorionic gonadotropin [β-hCG] test before 7 days of starting study treatment. Exclusion Criteria: History of other active malignancies within 1 years of study entry, with the exception of adequately treated in-situ carcinoma of cervix, localized basal cell or squamous cell carcinoma of skin, previous malignancy that was not recurred in 5 years; History of allogeneic or autologous stem cell transplant or chimeric antigen receptor-modified T-cell (CAR-T) therapy within the past 100 days before starting study treatment, or diagnosis of graft vs host disease; Clinically significant, uncontrolled cardiac or cardiovascular disease, or history of myocardial infarction, New York Heart Association (NYHA) Class III or IV, QTc prolongation (defined as a QTc > 450 ms) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min) ,within 6 months prior to planned start of MH048 treatment; Transformation (e.g., Richter's transformation, prolymphocytic leukemia, or blastoid lymphoma) prior to the planned start of MH048 treatment; Subjects with known or suspected history of allergy to MH048 capsules or excipients; Any unresolved toxicities from prior therapy of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v5.0) Grade 2 or higher at the time of starting MH048 treatment, with the exception of toxicities not considered a safety risk (eg, alopecia, neuropathy, or asymptomatic laboratory abnormalities); Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection; Active uncontrolled autoimmune disease; Clinically significant active malabsorption syndrome; Subjects with human immunodeficiency virus (HIV) , Active hepatitis B virus (HBsAg positive, or HBsAg negative/HBcAb positive ，and HBV DNA>10^3) or Active HCV infection (HCVAb positive ,and HCV RNA positive); Major surgery within 4 weeks prior to planned start of MH048 treatment (expect for biopsy, laser eye surgery)； Women of childbearing potential who are pregnant or lactating; Subjects requiring therapeutic anticoagulation; Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of MH048 treatment; Received a CYP3A4, CYP2A8 strong inhibitor or inducer within 5 half-lives of planned investigational product administration； Medical history of massive bleeding (hemophilia or other disease need the treatment of blood transfusion）; Severe neurological/mental illness, and in the opinion of the Investigator, is unable to adhere to the requirements of the study; Receipt of any investigational agent or clinical study within 28 days; Unstable brain metastasis patient.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Dose Escalation and Determination of RP2D<br>Part A: Dose Escalation and determination of RP2D, multiple dose levels of MH048 to be evaluated | Drug: MH048<br>* Soft gel capsules 5 mg and 25 mg，oral MH048 should be administered after an overnight fast.<br>* Other names: MH048 Soft Gel Capsules;|
| Experimental: Part B: Dose Expansion in Selected Relapsed/Refractory B-cell Malignancies<br>Part B: Selected relapsed/refractory B-NHL subjects with at least 1 prior systemic OR standard-of-care therapy. | Drug: MH048<br>* Soft gel capsules 5 mg and 25 mg，oral MH048 should be administered after an overnight fast.<br>* Other names: MH048 Soft Gel Capsules;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the incidence and severity of Treatment-Emergent Adverse Events [Safety and Tolerability] | Assess incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 | Up to approximately 24 Months | 
| To determine the MTD of MH048 | If 2 or more treated subjects at a dose level experience a DLT before Day 28, dose escalation will stop and the prior dose level will be considered the MTD for that schedule. | At the end of Cycle 1( 28 day) of each dose escalation cohort. | 
| To establish the RP2D. | The determination of RP2D for phase 2 according to the result of dose expansion cohorts. | Up to approximately 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of Pharmacokinetics (Cmax) | Maximum drug concentration (Cmax) | At the end of Cycle 1 (each cycle is 28 days) | 
| Characterization of Pharmacokinetics (AUC) | Area Under the Curve (AUC) | At the end of Cycle 1 (each cycle is 28 days) | 
| Characterization of Pharmacokinetics (CL) | Clearance (CL) | At the end of Cycle 1 (each cycle is 28 days) | 
| Characterization of Pharmacokinetics (t1/2) | Elimination half-life (t1/2) | At the end of Cycle 1 (each cycle is 28 days) | 
| Preliminary evidence of anti-tumor activity, in terms of Objective Response Rate (ORR) | The number (%) of subjects with best overall response (BoR) of CR or PR. | From date of enrollment until the date of best overall response (BoR) of CR or PR, assessed up to approximately 24 months. | 
| Preliminary evidence of anti-tumor activity, in terms of Duration of Response (DOR) | The duration from the first documentation of CR or PR to the first documented PD or death due to any cause, whichever occurs first. | From the first documented of CR or PR to the first documented PD or death due to any cause, whichever came first, , assessed up to approximately 24 months. |