Clinical Trials /

APG-115 in Patients With Advanced Solid Tumors or Lymphomas

NCT02935907

Description:

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.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: APG-115 in Patients With Advanced Solid Tumors or Lymphomas
  • Official Title: A Phase I Study of the Safety, Pharmacokinetic and Pharmacodynamic Properties of Orally Administered APG-115 in Patients With Advanced Solid Tumors or Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: APG-115-US-001
  • NCT ID: NCT02935907

Conditions

  • Patients With Advanced Solid Tumor or Lymphoma

Interventions

DrugSynonymsArms
APG-115APG-115

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
APG-115ExperimentalAPG-115 to be explored sequentially during accelerated dose escalation. This will continue until either the occurrence in Cycle 1 of one DLT or two Grade 2 toxicities (graded as per the National Cancer Institute's Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0) that are related or possibly related to APG-115. When either of these criteria is fulfilled, dose escalation will be converted to a standard 3+3 escalation scheme,
  • APG-115

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:28 days
Safety Issue:
Description:Patients with APG-115 treatment related adverse events (AE), serious adverse events (SAE) will be assessed according NCI CTCAE Version 4.0

Secondary Outcome Measures

Measure:Response will be evaluated every 2 cycles (8 weeks), according to the revised RECIST Guideline, Version 1.1
Time Frame:18-24 months
Safety Issue:
Description:
Measure:Maximum plasma concentration (Cmax) of APG-115 on Day 1-3 and Day 21-23 post APG-115 treatment on cycle 1
Time Frame:23 days
Safety Issue:
Description:
Measure:Area under the plasma concentration versus time curve (AUC) of APG-115 on Day 1 -3 and Day 21 - 23 post APG-115 treatment on cycle 1
Time Frame:23 days
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ascentage Pharma Group Inc.

Last Updated

October 14, 2016