Clinical trial NCT04689308: This is a Phase 1 Study of MH048 in Patients With Selected Relapsed/Refractory B-cell Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Relapsed/Refractory B-cell Malignancies
Lead sponsor: Minghui Pharmaceutical (Shanghai) LTD
Sponsor class: INDUSTRY
First posted: 2020-12-30
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female subjects ≥18 years of age;
2. Willing and able to understand and sign an informed consent form and to comply with all aspects of the protocol;
3. Life expectancy of ≥12 weeks;
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2;
5. 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;
6. There must be radiographically measurable disease for effects assess at dose expansion cohort;
7. 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 );
8. Willing to have bone marrow biopsy/aspirate for baseline disease assessment and assessment of response to treatment;
9. 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:

1. 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;
2. 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;
3. 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;
4. Transformation (e.g., Richter's transformation, prolymphocytic leukemia, or blastoid lymphoma) prior to the planned start of MH048 treatment;
5. Subjects with known or suspected history of allergy to MH048 capsules or excipients;
6. 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);
7. Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection;
8. Active uncontrolled autoimmune disease;
9. Clinically significant active malabsorption syndrome;
10. 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);
11. Major surgery within 4 weeks prior to planned start of MH048 treatment (expect for biopsy, laser eye surgery)；
12. Women of childbearing potential who are pregnant or lactating;
13. Subjects requiring therapeutic anticoagulation;
14. Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of MH048 treatment;
15. Received a CYP3A4, CYP2A8 strong inhibitor or inducer within 5 half-lives of planned investigational product administration；
16. Medical history of massive bleeding (hemophilia or other disease need the treatment of blood transfusion）;
17. Severe neurological/mental illness, and in the opinion of the Investigator, is unable to adhere to the requirements of the study;
18. Receipt of any investigational agent or clinical study within 28 days;
19. Unstable brain metastasis patient.

Primary outcomes:
measure: To evaluate the incidence and severity of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Up to approximately 24 Months
measure: To determine the MTD of MH048
timeFrame: At the end of Cycle 1( 28 day) of each dose escalation cohort.
measure: To establish the RP2D.
timeFrame: Up to approximately 24 Months
Secondary outcomes:
measure: Characterization of Pharmacokinetics (Cmax)
timeFrame: At the end of Cycle 1 (each cycle is 28 days)
measure: Characterization of Pharmacokinetics (AUC)
timeFrame: At the end of Cycle 1 (each cycle is 28 days)
measure: Characterization of Pharmacokinetics (CL)
timeFrame: At the end of Cycle 1 (each cycle is 28 days)
measure: Characterization of Pharmacokinetics (t1/2)
timeFrame: At the end of Cycle 1 (each cycle is 28 days)
measure: Preliminary evidence of anti-tumor activity, in terms of Objective Response Rate (ORR)
timeFrame: From date of enrollment until the date of best overall response (BoR) of CR or PR, assessed up to approximately 24 months.
measure: Preliminary evidence of anti-tumor activity, in terms of Duration of Response (DOR)
timeFrame: 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.
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: the First Affiliated Hospita，Medicine School of Zhejiang University
state: Zhejiang
Study officials:
affiliation: 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China
name: Jie Jin, MD
role: PRINCIPAL_INVESTIGATOR
References: