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APG-2449 in Patients With Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03917043
Recruitment Status : Recruiting
First Posted : April 16, 2019
Last Update Posted : April 8, 2022
Sponsor:
Collaborator:
Suzhou Yasheng Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Ascentage Pharma Group Inc.

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.

Condition or disease Intervention/treatment Phase
Advanced Solid Cancer Non Small Cell Lung Cancer Esophageal Cancer Ovarian Cancer Malignant Pleural Mesothelioma Drug: APG-2449 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: N/A
Intervention Model: Sequential Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of the Safety, Pharmacokinetic and Pharmacodynamic Properties of Orally Administered APG-2449 in Patients With Advanced Solid Tumors
Actual Study Start Date : May 27, 2019
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : February 2025


Arm Intervention/treatment
Experimental: APG-2449
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
Capsule, multiple dose cohorts, oral administration every day (QD) of a 28-day cycle
Other Name: APG-2449 Capsule




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: 28 days ]
    To determine the maximum tolerated dose (MTD) of APG-2449 in subjects with advanced solid tumors

  2. Recommended Phase 2 dose (RP2D) [ Time Frame: 28 days ]
    To determine the tentative recommended Phase 2 dose (RP2D) of APG-2449 in subjects with advanced solid tumors


Secondary Outcome Measures :
  1. Maximum plasma concentration (Cmax) [ Time Frame: 28 days ]
    Maximum plasma concentration (Cmax) will be assessed on all participants with APG-2449 treatments

  2. Area under the plasma concentration versus time curve (AUC) [ Time Frame: 28 days ]
    Area under the plasma concentration versus time curve (AUC) will be assessed on all participants with APG-2449 treatments

  3. Phosphorylation of FAK protein [ Time Frame: 28 days ]
    Phosphorylation of FAK protein will be assessed in peripheral blood mononuclear cells on all participants with APG-2449 treatments

  4. Preliminary efficacy assessment: Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: 4 weeks ]
    To assess preliminary efficacy in subjects with solid tumors using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 one, patients with non-small cell lung cancer who have progressed or intolerable after the second-generation ALK TKI(Alectinib or Ceritinib or Brigatinib or Ensartinib) or any ROSI TKI 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.

  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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03917043


Contacts
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Contact: Yifan Zhai, M.D., Ph.D. +86-20-28069260 yzhai@ascentage.com

Locations
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China, Beijing
Beijing Cancer Hospital Recruiting
Beijing, Beijing, China, 100142
Contact: Jun Zhao, M.D.       ohjerry@163.com   
Contact: Jian Fang, Ph.D.       fangjian5555@163.com   
Principal Investigator: Jun Zhao, M.D.         
Principal Investigator: Jian Fang, Ph.D.         
China, Fujian
Fujian Medical University Union Hospital Not yet recruiting
Fuzhou, Fujian, China, 350001
Contact: Xiaoyan Lin, Ph.D         
Principal Investigator: Xiaoyan Lin, Ph.D         
Fujian Cancer Hospital Not yet recruiting
Fuzhou, Fujian, China, 350014
Contact: Wu Zhuang, Ph.D         
Principal Investigator: Wu Zhuang, Ph.D         
China, Guangdong
Sun-Yat Sen University Cancer Center Recruiting
Guangzhou, Guangdong, China, 510060
Contact: LI ZHANG, Professor    +86-20-87343560    Zhangli@sysucc.cn   
The First affiliated hospital, Sun Yat-sen University Recruiting
Guangzhou, Guangdong, China
Contact: Yubiao Guo, Professor         
China, Henan
Henan Provincial Oncology Hospital Recruiting
Zhengzhou, Henan, China
Contact: Yanqiu Zhao, Professor         
China, Hubei
Union Hospital medical college Huazhong University of Science and Technology Recruiting
Wuhan, Hubei, China
Contact: Gang Wu, Professor         
China, Hunan
Hunan Provincial Oncology Hospital Recruiting
Changsha, Hunan, China
Contact: Jianhua Chen, Professor         
China, Sichuan
West China hospital of Sichuan University Not yet recruiting
Chengdu, Sichuan, China
Contact: Youling Gong, Professor         
China, Zhejiang
Zhejiang Provincial Oncology Hospital Recruiting
Hangzhou, Zhejiang, China
Contact: Yiping Zhang, Professor         
Sponsors and Collaborators
Ascentage Pharma Group Inc.
Suzhou Yasheng Pharmaceutical Co., Ltd.
Investigators
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Principal Investigator: Li Zhang, Professor Sun Yat-sen University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ascentage Pharma Group Inc.
ClinicalTrials.gov Identifier: NCT03917043    
Other Study ID Numbers: APG2449XC101
First Posted: April 16, 2019    Key Record Dates
Last Update Posted: April 8, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mesothelioma
Mesothelioma, Malignant
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Mesothelial
Pleural Neoplasms