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.
Inclusion Criteria:
1. 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.
2. Male or non-pregnant, non-lactating female patients age ≥18 years
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
4. Adequate hematologic and bone marrow functions
5. Adequate renal and liver function
6. Troponin (I) ≤ Upper Limit of Normal
7. 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.
8. 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.
9. 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).
10. Willingness and ability to comply with study procedures and follow-up examination.
11. 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.
12. Willingness to undergo tumor genotyping for P53 mutation at screening. Confirmation of
P53 non-mutant status is encouraged, but not required.
Exclusion Criteria:
1. Receiving concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
immunotherapy, hormonal therapy, targeted therapy, biologic therapy, with the
exception of hormones for hypothyroidism or estrogen replacement therapy (ERT), anti
estrogen analogs, agonists required to suppress serum testosterone levels); or any
investigational therapy within 14 days prior to the first dose of study drug.
2. Steroid therapy for anti-neoplastic intent within 7 days prior to the first dose of
study drug.
3. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that do not
recover to ≤ Grade 2.
4. Has gastrointestinal conditions that could affect the absorption of APG-115 in the
opinion of the Investigator.
5. Use of therapeutic doses of anti-coagulants is excluded, along with anti-platelet
agents; low-dose anticoagulation medications that are used to maintain the patency of
a central intravenous catheter are permitted.
6. Received a biologic (granulocyte colonystimulating factor, granulocyte-macrophage
colony-stimulating factor or erythropoietin) within 14 days prior to the first dose of
study drug.
7. 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.
8. Unstable angina, myocardial infarction, or a coronary revascularization procedure
within 180 days of study entry.
9. Neurologic instability per clinical evaluation due to tumor involvement of the central
nervous system (CNS). Patients with CNS tumors that have been treated, are
asymptomatic and who have discontinued steroids (for the treatment of CNS tumors) for
> 28 days may be enrolled.
10. Active symptomatic fungal, bacterial and/or viral infection including, but not limited
to, active human immunodeficiency virus (HIV) or viral hepatitis (B or C).
11. Diagnosis of fever and neutropenia within 1 week prior to study drug administration.
12. Uncontrolled concurrent illness including, but not limited to: serious uncontrolled
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
the study requirements.
13. Prior treatment with MDM2 inhibitors.
14. Any other condition or circumstance of that would, in the opinion of the investigator,
make the patient unsuitable for participation in the study.
