Clinical Trials /

A Study of APG-1252 in Patients With SCLC or Other Solid Tumors

NCT03080311

Description:

APG-1252 is a highly potent Bcl-2 family protein inhibitor, a promising drug candidate which shown high binding affinities to Bcl-2, Bcl-xL and Bcl-w. The preclinical studies have shown that APG-1252 alone achieves complete and persistent tumor regression in multiple tumor xenograft models with a twice weekly or weekly dose-schedule, including SCLC, colon, breast and ALL cancer xenografts; achieves strong synergy with the chemotherapeutic agents, indicating that APG-1252 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-1252 is intended for the treatment of patients with SCLC or other solid tumors. This is a multi-center, open-label, dose escalation Phase I study to determine the MTD and DLTs of intravenously administered APG-1252. After dose escalation to 240mg twice weekly, 2 dose cohorts two different dosing schedules including weekly and twice weekly will be assessed to evaluate for safety, tolerability, PK and preliminary anti-tumor efficacy. Treatment with APG-1252 will be administered to 30-60 patients at approximately 2 investigational sites in US.

Related Conditions:
  • Malignant Solid Tumor
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of APG-1252 in Patients With SCLC or Other Solid Tumors
  • Official Title: A Phase I Study of the Safety, Pharmacokinetic and Pharmacodynamic Properties of Intravenously Administered APG-1252 in Patients With Small Cell Lung Cancer (SCLC) or Other Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: APG-1252-US-001
  • NCT ID: NCT03080311

Conditions

  • Small Cell Lung Cancer and Other Solid Tumors

Interventions

DrugSynonymsArms
APG-1252APG-1252 for injectionAPG-1252

Purpose

APG-1252 is a highly potent Bcl-2 family protein inhibitor, a promising drug candidate which shown high binding affinities to Bcl-2, Bcl-xL and Bcl-w. The preclinical studies have shown that APG-1252 alone achieves complete and persistent tumor regression in multiple tumor xenograft models with a twice weekly or weekly dose-schedule, including SCLC, colon, breast and ALL cancer xenografts; achieves strong synergy with the chemotherapeutic agents, indicating that APG-1252 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-1252 is intended for the treatment of patients with SCLC or other solid tumors. This is a multi-center, open-label, dose escalation Phase I study to determine the MTD and DLTs of intravenously administered APG-1252. After dose escalation to 240mg twice weekly, 2 dose cohorts two different dosing schedules including weekly and twice weekly will be assessed to evaluate for safety, tolerability, PK and preliminary anti-tumor efficacy. Treatment with APG-1252 will be administered to 30-60 patients at approximately 2 investigational sites in US.

Detailed Description

      In dose cohort 1, patients will be treated in cycles, which are defined by APG-1252
      intravenous administration on Days 1, 4, 8, 11, 15, 18 and 22, over a 28-day cycle the start
      dose is 10mg.

      After dose escalation to 240mg twice weekly in dose cohort 1, dose cohort 2 will be performed
      with dose cohort 1 parallelly, patients will be treated in the same 28-day-cycles, APG-1252
      intravenous administration on Days 1, 8, 15, and 22, the start dose is 240mg.

      In both dose cohorts' patients could continue to receive cycles of APG-1252 until disease
      progress or unacceptable toxicity.

      Study drug will be administered by intravenous infusion for 30 minutes at the investigational
      site by site staff.
    

Trial Arms

NameTypeDescriptionInterventions
APG-1252ExperimentalAn accelerated dose escalation scheme will be utilized initially with one patient enrolled per cohort. If at 10 mg or 20 mg dose level, any occurrence in cycle 1 of one ≥ Grade 2 adverse event related or possibly related to APG-1252 (graded as per the National Cancer Institute's Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0) is the trigger for converting to a standard 3+3 design at that dose level.
  • APG-1252

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed small cell lung cancer (SCLC) or other solid
             tumors;

          2. Male or non-pregnant, non-lactating female patients age ≥18 years;

          3. Locally advanced or metastatic disease for which no standard therapy is judged
             appropriate by the investigator;

          4. Eastern Cooperative Oncology Group (ECOG) Performance Status < 2;

          5. Adequate hematologic function as indicated by:

               1. Platelet count ≥ 100,000/mm3

               2. Hemoglobin ≥ 9.0g/dL Platelet count ≥ 100,000/mm3

               3. Absolute neutrophil count (ANC) ≥1000/µL

          6. Adequate renal and liver function as indicated by:

               1. Serum creatinine ≤ 1.5 x upper limit of normal (ULN); if serum creatinine is >1.5
                  X ULN, creatinine clearance must be ≥ 50 mL/min (see Section 22.3).

               2. Total bilirubin ≤1.5 x ULN; If Gilbert's Syndrome may have Bilirubin> 1.5 x ULN

               3. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤3 x ULN of
                  institution's normal range; for patients with known liver metastases, AST and ALT
                  may be ≤ 5 x ULN.

               4. Coagulation: aPTT and PT<1.2 x the 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.

        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, or has had tumor embolization or tumor lysis syndrome (TLS)
             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. Known bleeding diathesis/disorder;

          5. Recent history of non-chemotherapy induced thrombocytopenia associated bleeding within
             1 year prior to first dose of study drug.

          6. Have active immune thrombocytopenic purpura (ITP), active autoimmune hemolytic anemia
             (AIHA), or a history of being refractory to platelet transfusions (within 1 year prior
             to the first dose of study drug).

          7. Serious gastrointestinal bleeding within 3 months;

          8. 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.

          9. Received a biologic (G-CSF, GM-CSF or erythropoietin) within 28 days prior to the
             first dose of study drug.

         10. 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;

         11. Unstable angina, myocardial infarction, or a coronary revascularization procedure
             within 180 days of study entry.

         12. 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;

         13. Active symptomatic fungal, bacterial and/or viral infection including, but not limited
             to, active human immunodeficiency virus (HIV) or viral hepatitis (B or C);

         14. Diagnosis of fever and neutropenia within 1 week prior to study drug administration.

         15. 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.

         16. Prior treatment with Bcl-2/Bcl-xL inhibitors.

         17. Any other condition or circumstance of that would, in the opinion of the investigator,
             make the patient unsuitable for participation in the study.

         18. Known clinically active hepatitis B or hepatitis C infection. Testing for hepatitis B
             and C is not required for study enrollment.

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

Primary Outcome Measures

Measure:Dose limit toxicity (DLT) determination
Time Frame:18 - 24 months
Safety Issue:
Description:Number of participants with APG-1252 treatment-related adverse events as assessed by CTCAE v4.0

Secondary Outcome Measures

Measure:Pharmacokinetic evaluation
Time Frame:18 - 24 months
Safety Issue:
Description:Peak plasma concentration (Cmax) will be assessed on all participants with APG-1252 treatments
Measure:Pharmacokinetic evaluation
Time Frame:18 - 24 months
Safety Issue:
Description:Area under the plasma concentration versus time curve (AUC) will be assessed on all participants with APG-1252 treatments
Measure:Pharmacodynamic evaluation
Time Frame:18-24 months
Safety Issue:
Description:Platelet counts will be measured on the participants with APG-1252 treatments
Measure:Pharmacodynamic evaluation
Time Frame:18-24 months
Safety Issue:
Description:Bcl-2 protein in PBMCs will be measured on the participants with APG-1252 treatments
Measure:Pharmacodynamic evaluation
Time Frame:18-24 months
Safety Issue:
Description:Activation of apoptosis will be measured on the participants with APG-1252 treatments
Measure:Preliminary efficacy assessment
Time Frame:18-24 months
Safety Issue:
Description:Patients will be evaluated for response every 2 cycles (i.e., 8 weeks), according to the new response evaluation criteria in solid tumors: revised RECIST Guideline, Version 1.1

Details

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

Trial Keywords

  • Bcl-2/Bcl-xL dual inhibitor

Last Updated

March 13, 2019