A Phase I/II, Open-label Study to Investigate the Safety, Tolerability, PK, and Preliminary Efficacy of FB849

Study Overview
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Brief Summary
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This is the first-in-human, multicenter, open-label Phase I/II study to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of FB849 alone and in combination with pembrolizumab in subjects with advanced solid tumors for whom no standard therapy is available.

Detailed Description
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The study will be conducted in 2 parts: Phase I dose-escalation part and Phase II efficacy-assessment part both in monotherapy and in combination with pembrolizumab. The Phase I dose-escalation part will use an adaptive study design termed Bayesian optimal interval (BOIN) design to investigate the safety and tolerability of FB849 and determine the maximum tolerated dose and recommended Phase II dose (RP2D) of FB849. A BOIN design is a hybrid of rule-based and model-based design, which has the flexibility of dose escalation and de-escalation and allows more subjects to be enrolled into the doses closest to the target toxicity rate. The Phase II-part enrollment will be initiated once the RP2D has been determined in the Phase I part. It will evaluate FB849 at the RP2D alone and ≥1 dose lower than the RP2D in combination with a standard dose of pembrolizumab to provide assessments of safety, PK, and anti-tumor activity of FB849. It will also explore the impact of FB849 on pharmacodynamics and metabolites. In this part of the study, subjects with advanced refractory solid tumors, Type A cancer, Type B cancer, Type C cancer will be enrolled in 4 cohorts. Enrollment to these cohorts will follow a Simon's two-stage design enrollment. Response assessments will be based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines.

Official Title
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A Phase I/II, Open-label Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of FB849 Administered in Subjects With Advanced Solid Tumors Alone and in Combination With Pembrolizumab

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: FB849
* Drug: FB849 Monotherapy
* Drug: FB849 in Combination with Pembrolizumab (Type A cancer)
* Drug: FB849 in Combination with Pembrolizumab (Type B cancer)
* Drug: FB849 in Combination with Pembrolizumab (Type C cancer)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject should understand, sign, and date the written ICF prior to screening. Male or female aged 18 years or older. Subjects must have at least 1 measurable target lesion according to RECIST version 1.1. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Life expectancy ≥ 3 months in the opinion of the investigator. Adequate organ function and bone marrow function as indicated by the following screening assessments performed within 14 days prior to the first dose of study treatment Exclusion Criteria: Known allergy or hypersensitivity to any component of the study treatment. Has a known additional malignancy that is progressing or has required active treatment. Has abnormal or inadequately controlled endocrine function. Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption of oral medication. Previous anti-cancer therapy, including chemotherapy (chemotherapy with nitrosourea or mitomycin should be at least 6 weeks prior to initiation of study treatment), radiotherapy, molecular targeted therapy, or other investigational drugs received ≤ 4 weeks; endocrine therapy ≤ 2 weeks or ≤ 5-half-lives (whichever is shorter) prior to initiation of study treatment.

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: Single Group Assignment
Interventional Model Description: The study will be conducted in 2 parts: Phase I dose-escalation part and Phase II efficacy-assessment part both in monotherapy and in combination with pembrolizumab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort<br>Participations will received FB849 orally once a day. | Drug: FB849<br>* At a given level dose once daily<br>|
| Experimental: Dose Expansion Cohort - FB849 Monotherapy<br>Participations will received FB849 orally once a day. | Drug: FB849 Monotherapy<br>* At recommended dose for expansion cohort once daily<br>* Other names: FB849;|
| Experimental: Dose Expansion Cohort - FB849 in Combination with Pembrolizumab (Type A cancer)<br>Participations will received FB849 orally once a day in combination with pembrolizumab. | Drug: FB849 in Combination with Pembrolizumab (Type A cancer)<br>* At recommended dose for expansion cohort once daily in combination with pembrolizumab<br>* Other names: FB849;|
| Experimental: Dose Expansion Cohort - FB849 in Combination with Pembrolizumab (Type B cancer)<br>Participations will received FB849 orally once a day in combination with pembrolizumab. | Drug: FB849 in Combination with Pembrolizumab (Type B cancer)<br>* At recommended dose for expansion cohort once daily in combination with pembrolizumab<br>* Other names: FB849;|
| Experimental: Dose Expansion Cohort - FB849 in Combination with Pembrolizumab (Type C cancer)<br>Participations will received FB849 orally once a day in combination with pembrolizumab. | Drug: FB849 in Combination with Pembrolizumab (Type C cancer)<br>* At recommended dose for expansion cohort once daily in combination with pembrolizumab<br>* Other names: FB849;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and tolerability of FB849 and to identify maximum tolerated dose (MTD)/ recommended Phase II dose (RP2D) and dosing schedule of FB849 in subjects with advanced solid tumors | The MTD is defined to be the highest safe dose with an estimated DLT rate less than 30. | DLT Assessment at the end of Cycle 1(each cycle is 21 days.) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the pharmacokinetic parameters such as Peak Plasma Concentration (Cmax) of FB849 | The PK parameters should include, where appropriate, area under the concentration-time curve (AUC), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), and apparent terminal elimination half-life (t1/2), apparent total body clearance (CL/F), apparent volume of distribution (Vz/F), Cmax at steady state (Css-max), minimum observed concentration at steady state (Css-min), AUC at steady state (AUCss), accumulation ratio (Rac), amount excretion (Ae), fraction excretion (Fe), renal clearance (CLR). | Blood: Predose, 1, 2, 4, 8, 12, 24 hrs postdose at C1D1 and C1D21; predose and 4, 8, and 24 hrs postdose at C1D8; predose at C1D15; and predose on C2D1, C4D1, and C6D1, Urine: predose and 0-4 hr, 4-8 hr, 8-12 hr, 12-24 hr post-dose | 
| To assess preliminary anti-tumor activity of FB849 | Tumor response will be assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen/pelvis, and additional assessments (e.g., craniocerebral imaging, bone scan) based on clinical indications. | every 6 weeks (± 3 days) in the first 18 weeks, then every 12 weeks (± 7 days) thereafter until disease progression |