APG-2449 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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APG-2449 is a novel, orally active, multi-targeted tyrosine kinase inhibitor, which inhibits FAK, ALK, and ROS1 with nanomolar potencies. In preclinical studies, APG-2449 demonstrated potent antiproliferative activity in various cancer cell lines as a single agent. In combination treatment, APG-2449 enhanced anti-proliferative activities of several chemotherapeutic and targeted agents. It is indicated that APG-2449 may have a broad therapeutic potential for the treatment of human cancer as a single agent and in combination with other classes of anticancer drugs. APG-2449 is intended for the treatment of patients with advanced solid tumors. Upon completion of the Phase 1 dose escalation study to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and/or recommended phase 2 dose (RP2D), several phase Ib/II studies will be implemented accordingly.

Official Title
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A Phase I Study of the Safety, Pharmacokinetic and Pharmacodynamic Properties of Orally Administered APG-2449 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Cancer, Non Small Cell Lung Cancer, Esophageal Cancer, Ovarian Cancer, Malignant Pleural Mesothelioma

Intervention / Treatment
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* Drug: APG-2449


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose exploration stage: non-small cell lung cancer diagnosed by histology and/or cytology and positive for ALK/ROS1 gene fusion (molecular diagnosis confirmed by the investigator) and malignant pleural mesothelioma, esophageal cancer and ovarian cancer. Kind of patients with advanced tumors. Expansion stage: cohort one, Patients with non-small cell lung cancer who have progressed or are not tolerated on second-generation ALK TKI therapy or any ROS1 TKI therapy treatment ; cohort two, ALK/ROS1 fusion gene positive without TKI treatment Patients with non-small cell lung cancer. The molecular diagnosis results of the above patients can be confirmed by the investigator. ECOG Performance Status ≤ 1. Expectation of life ≥ 3 months. According to RECIST version 1.1, there is at least 1 measurable lesion. Adequate hematologic and bone marrow functions. Adequate renal and liver function. Normal cardiac function. Brain metastases with clinically controlled neurologic symptoms. Serum pregnancy test results of women of childbearing age were negative within 7 days before taking the first dose of study drug. Men, women of childbearing age (postmenopausal women must have been menopausal for at least 12 months before they can be considered infertile) and their partners voluntarily take the study drug for at least 30 days after signing the informed consent form and taking the study drug as deemed effective by the investigator Contraceptive measures Ability to understand and willingness to sign a written informed consent form Subjects must be willing and able to complete the research procedures and follow-up inspections. Subjects are required to provide fresh (for recurrent subjects only) or archived tumor tissue samples from within 28 days prior to treatment. If none of these specimens are available, they may be included after consultation with the sponsor. Exclusion Criteria: Receiving concurrent anti-cancer therapy (chemotherapy, radiotherapy, immunotherapy, biologic therapy); or any investigational therapy within 28 days prior to the first dose of study drug. Receiving TKI therapy within 8 days prior to the first dose of study drug. Continuance of toxicities due to prior therapy that do not recover (CTCAE V5.0 Grade> 1). Has difficulty in swallowing, absorbing barrier, or other diseases blocking APG-2449' taken. Obvious cardiovascular disease history. Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients who have had major surgery within 28 days from study entry, and patients who have had minor surgery within 14 days of study entry. Active symptomatic fungal, bacterial and/or viral infection including, but not limited to, active human immunodeficiency virus (HIV) or viral hepatitis (B or C). Known allergies to study drug ingredients or their analogs. Female subjects who are pregnant or breastfeeding, or expecting to become pregnant during the study period. According to the judgment of the investigator or sponsor, any symptoms or disease of the subject may endanger its safety or interfere with the safety assessment of the study drug. Subjects who have used CYP3A4, CYP2C9, or CYP2C19 moderately potent inhibitors or moderately potent inducers 1 week before receiving the study drug for the first time. Subjects who used CYP3A4 substrates and narrow treatment window 1 week before the first study drug.

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: Sequential Assignment
Interventional Model Description: Dose escalation of APG-2449 will use standard 3+3 design. The starting dose is 150 mg and will be increased in subsequent cohorts to 300mg, 450mg, 600mg, 750mg, 900mg, 1200mg and 1500mg, accordingly.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG-2449<br>APG-2449 will be explored sequentially using a standard 3+3 escalation scheme at the dose escalation phase and up to 30-40 patient at the MTD/RP2D dose level. | Drug: APG-2449<br>* Capsule, multiple dose cohorts, oral administration every day (QD) of a 28-day cycle<br>* Other names: APG-2449 Capsule;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | To determine the maximum tolerated dose (MTD) of APG-2449 in subjects with advanced solid tumors | 28 days | 
| Recommended Phase 2 dose (RP2D) | To determine the tentative recommended Phase 2 dose (RP2D) of APG-2449 in subjects with advanced solid tumors | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) | Maximum plasma concentration (Cmax) will be assessed on all participants with APG-2449 treatments | 28 days | 
| Area under the plasma concentration versus time curve (AUC) | Area under the plasma concentration versus time curve (AUC) will be assessed on all participants with APG-2449 treatments | 28 days | 
| Phosphorylation of FAK protein | Phosphorylation of FAK protein will be assessed in peripheral blood mononuclear cells on all participants with APG-2449 treatments | 28 days | 
| Preliminary efficacy assessment: Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 | To assess preliminary efficacy in subjects with solid tumors using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 | 4 weeks |