A First-in-Human, JAB-8263 in Adult Patients With Advanced Tumors

Study Overview
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Brief Summary
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This is a Phase 1/2a, first-in-human, open-label study of JAB-8263, this study has two parts: solid tumor dose escalation and expansion study and hematology tumor dose escalation and expansion study. These two parts will determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) and assess the DLT of JAB-8263 in treatment with patients with advanced solid tumors and hematology tumors separately. 30 subjects each will be enrolled.

Detailed Description
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JAB-8263 is a small-molecule inhibitor of the highly conserved bromodomain pockets of the bromodomain and extraterminal (BET) proteins. The objectives of this study are: To determine the maximum-tolerated dose (MTD) and assess the dose-limiting toxicity (DLT) of JAB-8263 as a single agent to adult subjects with advanced malignant tumors. To assess the safety and tolerability of JAB-8263 To characterize the pharmacokinetic (PK) parameters and pharmacodynamics (PDc).To evaluate preliminary antitumor activity of JAB-8263

Official Title
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A Phase I/IIa, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Evidence of Antitumor Activity of JAB-8263 in Adult Patients With Advanced Malignant Tumors

Conditions
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NSCLC, SCLC, CRPC, ESCC, Ovarian Carcinoma, AML, MF, Malignant Tumor

Intervention / Treatment
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* Drug: JAB-8263
* Drug: JAB-8263


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all the following criteria in order to be included in the research study: Subject must be ≥18 years-of-age at the time of signature of the informed consent form (ICF). Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Subjects with histologically or cytologically confirmed advanced solid tumors which have progressed despite standard therapy(ies), or are intolerant to standard therapy(ies), or have a tumor for which no standard therapy(ies) exists. Subjects with recurrent/refractory AML according to WHO 2016 Subjects with life expectancy ≥3 months. Patients with solid tumor must have at least one measurable lesion as defined by RECIST v1.1. Patients who have sufficient baseline organ function. Exclusion Criteria: History (≤3 years) of cancer that is histologically distinct from the cancer under study. Known serious allergy to investigational drug or excipients Active brain or spinal metastases History of pericarditis or Grade ≥2 pericardial effusion History of interstitial lung disease. History of Grade ≥2 active infections within 2 weeks Known human immunodeficiency virus (HIV) infection Seropositive for hepatitis B virus (HBV) Seropositive for hepatitis C virus (HCV), or HCV-RNA viral levels are not detectable. Any severe and/or uncontrolled medical conditions History of myocardial infarction, unstable angina pectoris, coronary artery bypass graft, or cerebrovascular accident Impaired cardiac function or clinically significant cardiac diseases QTcF >470 msec at screening History of medically significant thromboembolic events or bleeding diathesis Unresolved Grade >1 toxicity History of malignant biliary obstruction Pregnant or breast-feeding

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: JAB-8263 Part1<br>Monotherapy, dose escalation | Drug: JAB-8263<br>* Variable dose, orally Q2D with 28 days each cycle<br>|
| Experimental: JAB-8263 Part 2<br>Monotherapy, dose expansion | Drug: JAB-8263<br>* RP2D dose, orally Q2D with 28 days each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities | Incidence of dose limiting toxicities (DLTs) in the dose escalation phase. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first treatment cycle with JAB-8263 | Approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs, electrocardiograms, cardiac imaging and ophthalmological assessments | Approximately 18 months | 
| Area under the curve | Area under the plasma concentration time curve of JAB-8263 | Approximately 18 months | 
| Cmax | Highest observed plasma concentration of JAB-8263 | Approximately 18 months | 
| Tmax | Time of highest observed plasma concentration of JAB-8263 | Approximately 18 months | 
| T1/2 | Half life of JAB-8263 | Approximately 18 months | 
| Objective response rate ( ORR ) | For solid tumor study part, ORR is defined as the proportion of participants with complete response or partial response (CR+PR) | Approximately 18 months | 
| Duration of response ( DOR ) | For solid tumor study part, DOR is defined as the time from the participant's initial objective response (CR or PR) to study drug therapy, to disease progression or death due to any cause, whichever occurs first. | Approximately 18 months | 
| Duration of response ( DCR ) | For solid tumor study part, DCR is defined as proportion of participants with complete response, partial response, stable disease(CR+PR+SD). | Approximately 18 months | 
| CR without minimal residual disease rate (CR MRD-) | hematology study part, CR MRD- is defined as proportion of participants with complete response without minimal residual disease. | Approximately 18 months | 
| Overall response rate | For hematology study part, Overall response rate is defined as proportion of participants with complete response(CR or CRi), partial remission(PR) or morphologic leukemia-free state(MLFS). | Approximately 18 months | 
| Event-free survival( EFS) | For hematology study part, EFS is defined for all patients with AML, measured from the date of entry into the study to the date of primary refractory disease, or relapse from CR, or Cri, or death from any cause. | Approximately 18 months |