A Phase I Study of the Safety, Pharmacokinetic and Pharmacodynamic Properties of Orally Administered APG-115 in Patients With Advanced Solid Tumors or Lymphomas
APG-115 is a novel, orally active small-molecule mouse double minute 2 homolog (MDM2) inhibitor. Mechanistically, APG-115 increases p53 and p21 overexpression, activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. APG-115 has shown strong dose- and schedule-dependent antitumor activities in multiple human cancer xenograft and a patient derived xenograft (PDX) models. The preclinical data generated from APG-115 suggest that it 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-115 is intended for the treatment of patients with advanced solid tumors and lymphomas. 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.
• Histologically or cytologically confirmed locally advanced or metastatic solid tumor or lymphoma that has relapsed from or is refractory to standard treatment, or no standard treatment is available. Only patients with advanced/metastatic cancer who have disease progression after treatment with all available therapies that are known to confer clinical benefit.
• Male or non-pregnant, non-lactating female patients age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
• Adequate hematologic and bone marrow functions
• Adequate renal and liver function
• Troponin (I) ≤ Upper Limit of Normal
• Brain metastases with clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 21 days of stable neurologic function \& no evidence of CNS disease progression as determined by CT or MRI within 21 days prior to the first dose of study drug.
• Willingness to use contraception by a method that is deemed effective by the investigator by both males and female patients of child bearing potential (postmenopausal women must have been amenorrheal for at least 12 months to be considered of non-childbearing potential) and their partners throughout the treatment period and for at least three months following the last dose of study drug.
• Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures).
⁃ Willingness and ability to comply with study procedures and follow-up examination.
⁃ Willingness to provide and there is confirmed availability of pre-existing diagnostic or resected tumor samples, such as paraffin-embedded sections. Providing fresh tumor biopsy is optional for subjects in dose escalation cohorts.
⁃ Willingness to undergo tumor genotyping for P53 mutation at screening. Confirmation of P53 non-mutant status is encouraged, but not required.