Clinical trial NCT03917043: APG-2449 in Patients With Advanced Solid Tumors
Official title: A Phase I Study of the Safety, Pharmacokinetic and Pharmacodynamic Properties of Orally Administered APG-2449 in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Cancer
Non Small Cell Lung Cancer
Esophageal Cancer
Ovarian Cancer
Malignant Pleural Mesothelioma
Lead sponsor: Ascentage Pharma Group Inc.
Sponsor class: INDUSTRY
Collaborators: name: Suzhou Yasheng Pharmaceutical Co., Ltd.
First posted: 2019-04-16
Enrollment: 165
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. 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 1, patients with non-small cell lung cancer who have progressed or are intolerant to TKI therapy, including patients with second-generation ALK TKI, or either ROS1 TKI, or third-generation ALK inhibitor (lorlatinib, etc.) with pFAK expression (pFAK expression is subject to central laboratory results) of about 10 or above; Cohort 2, TKI-naïve patients with ALK/ROS1 fusion gene positive NSCLC. The molecular diagnosis results of the above patients can be confirmed by the investigator.
2. ECOG Performance Status ≤ 1.
3. Expectation of life ≥ 3 months.
4. According to RECIST version 1.1, there is at least 1 measurable lesion.
5. Adequate hematologic and bone marrow functions.
6. Adequate renal and liver function.
7. Normal cardiac function.
8. Brain metastases with clinically controlled neurologic symptoms.
9. Serum pregnancy test results of women of childbearing age were negative within 7 days before taking the first dose of study drug.
10. 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
11. Ability to understand and willingness to sign a written informed consent form
12. Subjects must be willing and able to complete the research procedures and follow-up inspections.
13. 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.
14. Subjects should provide fresh biopsy tumor tissue specimens prior to treatment.

Exclusion Criteria:

1. 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.
2. Receiving TKI therapy within 8 days prior to the first dose of study drug.
3. Continuance of toxicities due to prior therapy that do not recover (CTCAE V5.0 Grade\> 1).
4. Has difficulty in swallowing, absorbing barrier, or other diseases blocking APG-2449' taken.
5. Obvious cardiovascular disease history.
6. 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.
7. Active symptomatic fungal, bacterial and/or viral infection including, but not limited to, active human immunodeficiency virus (HIV) or viral hepatitis (B or C).
8. Known allergies to study drug ingredients or their analogs.
9. Female subjects who are pregnant or breastfeeding, or expecting to become pregnant during the study period.
10. 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.
11. 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.
12. Subjects who used CYP3A4 substrates and narrow treatment window 1 week before the first study drug.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: 28 days
measure: Recommended Phase 2 dose (RP2D)
timeFrame: 28 days
Secondary outcomes:
measure: Maximum plasma concentration (Cmax)
timeFrame: 28 days
measure: Area under the plasma concentration versus time curve (AUC)
timeFrame: 28 days
measure: Phosphorylation of FAK protein
timeFrame: 28 days
measure: Preliminary efficacy assessment: Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Fuzhou
country: China
facility: Fujian Cancer Hospital
state: Fujian
city: Guangzhou
country: China
facility: Sun-Yat Sen University Cancer Center
state: Guangdong
city: Guangzhou
country: China
facility: The First affiliated hospital, Sun Yat-sen University
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Provincial Oncology Hospital
state: Henan
city: Wuhan
country: China
facility: Union Hospital medical college Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Hunan Provincial Oncology Hospital
state: Hunan
city: Hangzhou
country: China
facility: Zhejiang Provincial Oncology Hospital
state: Zhejiang
Study officials:
affiliation: Sun Yat-sen University
name: Li Zhang, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fang DD, Tao R, Wang G, Li Y, Zhang K, Xu C, Zhai G, Wang Q, Wang J, Tang C, Min P, Xiong D, Chen J, Wang S, Yang D, Zhai Y. Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models. BMC Cancer. 2022 Jul 11;22(1):752. doi: 10.1186/s12885-022-09799-4.