Clinical Trials /

Study of APG-2575 as a Single Agent or in Combination With Other Therapeutic Agents for CLL/SLL

NCT04215809

Description:

Assess the safety and tolerability, identify dose-limiting toxicities (DLT) and determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of APG-2575.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of APG-2575 as a Single Agent or in Combination With Other Therapeutic Agents for CLL/SLL
  • Official Title: APG-2575CU101, A Phase Ib Study of APG-2575 as a Single Agent or in Combination With Other Therapeutic Agents in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL

Clinical Trial IDs

  • ORG STUDY ID: APG2575CU101
  • NCT ID: NCT04215809

Conditions

  • CLL/SLL

Interventions

DrugSynonymsArms
APG2575APG 2575 600mg

Purpose

Assess the safety and tolerability, identify dose-limiting toxicities (DLT) and determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of APG-2575.

Detailed Description

      The study will be conducted in two (2) parts and each part will consist of a ramp-up period,
      dose escalation and dose expansion portions. The duration of the ramp-up period will depend
      on the dose schedule being tested and will be conducted for both monotherapy and combination
      therapy. The ramp-up will consist of treatment with APG-2575 given once a day starting at 20
      mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5¸ 600 mg on Day
      6, 800 mg on Day 7, 1000 mg on Day 8 and 1200 mg on Day 9. Scheduled maximum cohort doses for
      evaluation will start at 200 mg of APG-2575 to a maximum of 1200 mg of APG-2575.
      Consequently, patients with a scheduled maximum dose of 200 mg will have a 3-day ramp-up
      period, those scheduled at 400 mg, a 4-day ramp-up, and those scheduled at 600 mg, a 5-day
      ramp-up, etc, see Figure 1. Part 1 will study APG-2575 at different dose levels as
      monotherapy using a 3+3 dose escalation design with dose expansion at RP2D. Part 2 will be
      combination of APG-2575 with rituximab or acalabrutinib or voruciclib Part 2 will be a 3+3
      dose escalation of combination APG-2575 plus rituximab or acalabrutinib or voruciclib.
      Expansion cohorts at RP2D for the respective combinations will be conducted to further
      evaluate safety and anticancer activity
    

Trial Arms

NameTypeDescriptionInterventions
APG2575 200mgExperimentalAPG2575 200mg ramp up
  • APG2575
APG2575 400mgExperimentalAPG2575 400mg ramp up
  • APG2575
APG 2575 600mgExperimentalAPG2575 600mg ramp up
  • APG2575
APG2575 800mgExperimentalAPG2575 800mg ramp up
  • APG2575
APG2575 1000 mgExperimentalAPG2575 1000 mg ramp up
  • APG2575
APG2575 1200mgExperimentalAPG2575 1200mg ramp up
  • APG2575

Eligibility Criteria

        Inclusion Criteria:

          -  1. ≥18 years of age. 2. Histologically confirmed chronic lymphocytic leukemia (CLL) or
             small lymphocytic leukemia (SLL) according to the 2018 international workshop (IW) CLL
             criteria who must have relapsed or be refractory to at least one prior therapy for
             CLL/SLL and require treatment by 2018 IWCLL criteria.

             3. ECOG) ≤2. 4. Patient must have objectively documented evidence of disease
             progression prior to study entry such as: escalating lymphocytes count with an
             increase > 50% over a period of two months or doubling time in less than 6 months;
             enlarging adenopathy or splenomegaly; increasing cytopenias; clinical B symptoms
             -night sweats, fatigue, > 1% weight loss in 6 months, fevers > 100.50F for ≥ one month
             without infection.

             5. In Part 1 of the APG-2575 monotherapy dose escalation portion, patients eligible
             for dose expansion at doses lower than MTD will have received ≤ 3 prior systemic lines
             of therapy.

             6. Adequate bone marrow function independent of growth factor:

               1. Absolute neutrophil count (ANC)≥1.0× 109/L in patient without bone marrow
                  involvement. This criterion does not apply to patients with bone marrow
                  involvement by CLL/SLL.

               2. Platelets count ≥30 x 109/L (entry platelet count must be independent of
                  transfusion within 7 days of first dose of study drug).

                  7. Adequate renal and hepatic function as indicated by:

             a. Serum creatinine ≤1.5×upper limit of normal (ULN); if serum creatinine is >1.5×ULN,
             creatinine clearance must be ≥ 50 mL/min, calculated using the Cockcroft and Gault
             formula(140-Age)x mas (kg)/(72x creatinine mg/dL); multiply by 0.85 if female
             (Cockcroft 1976) b. Total bilirubin ≤1.5 x ULN, except patients with known Gilbert's
             syndrome. c. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2.5
             x ULN, Alkaline phosphatase<2.5×ULN d. International normalized Ratio (INR),
             Prothrombin Time (PT) or Activated Partial Thromboplastin time (APTT)≤1.5×ULN unless
             the patient is receiving anticoagulant therapy as long as PT or APTT is within
             therapeutic range of intended use of anticoagulants.

             8. Females of childbearing potential (i.e. not postmenopausal for at least 2 years or
             surgically sterile) must have negative results for pregnancy test performed:

             a. At Screening on a serum sample obtained within 14 days prior to the first study
             drug administration b. Prior to dosing on a urine sample obtained on the first day of
             study drug administration, if it has been>7 days since obtaining the serum pregnancy
             test results.

             9. Females of childbearing potential and non-sterile males must practice at least one
             of the following methods of birth control with partner(s) throughout the study and for
             90 days after discontinuing study drug:

               1. Total abstinence from sexual intercourse as the preferred lifestyle of the
                  patient; periodic abstinence is not acceptable;

               2. Surgically sterile partner(s); acceptable sterility surgeries are: vasectomy,
                  bilateral tubal ligation, bilateral oophorectomy or hysterectomy;

               3. Intrauterine device (IUD);

               4. Double-barrier method (contraceptive sponge, diaphragm or cervical cap with
                  spermicidal fellies or cream AND a condom);

               5. Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at
                  least 3 months prior to study drug administration.

                  If hormonal contraceptives are used, the specific contraceptive must have been
                  used for at least 3 months prior to study drug administration.

                  10. Male patients must refrain from sperm donation, from initial study drug
                  administration until 90 days after the last dose of study drug.

                  11. 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).

                  12. Willingness and ability to comply with study procedures and follow-up
                  examination.

                  Exclusion Criteria:

          -  1. Patient has undergone allogeneic stem cell transplant < 90 days 2. Patient has
             active graft-versus-host disease or require immunosuppressive therapy.

             3. Richter's Syndrome. 4. Prior anti-Bcl-2 treatment (except patients who discontinued
             treatment for reasons other than disease progression) 5. For combination cohorts:

               1. In the acalabrutinib and APG-2575 cohort, patients who are on anticoagulants or
                  patients that discontinued due to acalabrutinib toxicity (Note: Patients who
                  received a BTK inhibitor therapy may participate whether, or not, they progressed
                  following BTK inhibitor treatment).

               2. Prior CDK-9 inhibitor in the voruciclib plus APG-2575 cohort 6. Known human
                  immunodeficiency virus syndrome (HIV) infection 7. Known active hepatitis B
                  infection, as defined seropositivity for Hep B surface antigen (HBsAg) or known
                  hepatitis C infection as determined by hepatitis C antibody with elevated liver
                  enzymes as defined in the inclusion criteria or any other evidence of active
                  hepatitis C such as currently on treatment 8. Has known central nervous system
                  (CNS) involvement. 9. Prior malignancy that required treatment and has shown
                  recurrence within 2 years of screening (except for non-melanoma skin cancer or
                  adequately treated carcinoma in situ of cervix or breast). Cancer treated within
                  2 years with curative intent and without recurrence as well as prostate cancer on
                  active surveillance are allowed.

                  10. Concurrent treatment with an investigational agent, received biologics (≤28
                  days), or small molecule targeted therapies (≤5 half-life) or other anti-cancer
                  therapies (including chemotherapy) ≤14 days of first dose of study drug 11.
                  Patient is pregnant or breast feeding 12. Has received the following within 7
                  days prior to the first dose of study drug:

               1. Steroid therapy at a dose greater than prednisone 20 mg daily (or equivalent) for
                  anti-neoplastic intent;

               2. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin;

               3. Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's
                  wort; 13. Radiation within 14 days of study entry 14. Continuance of toxicities
                  due to prior radiotherapy or chemotherapy agents that have not recovered to ≤
                  grade 1 or baseline, except alopecia or neuropathy.

                  15. Failure to recover adequately, as judged by the investigator, from prior
                  surgical procedures. Patient with active wound healing, patients who have had
                  major surgery within 28 days from 1st dose of study drug 16. Has a cardiovascular
                  disability status of New York Heart Association Class ≥ 2. Class 2 is defined as
                  cardiac disease in which patients are comfortable at rest but ordinary physical
                  activity results in fatigue, palpitations, dyspnea or anginal pain.

                  17. Unstable angina or myocardial infarction within 3 months of enrollment 18.
                  QTc interval> 480ms (Bazett or Fredericia formulae) or other remarkable abnormal
                  ECG findings, including second-degree type II atrioventricular block,
                  third-degree atrioventricular block or bradycardia (ventricular rate of less than
                  50 beats per minute).

                  19. Has gastrointestinal conditions that could affect the absorption of APG-2575
                  in the opinion of the Investigator.

                  20. Uncontrolled concurrent illness including, but not limited to: uncontrolled
                  diabetes mellitus, symptomatic congestive heart failure, unstable angina
                  pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
                  limit compliance with the study requirements.

                  21. Any other condition or circumstance that would, in the opinion of the
                  investigator, make the patient unsuitable for participation in the study.
      
Maximum Eligible Age:85 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Primary Toxicity Endpoint: dose limiting toxicity (DLT)
Time Frame:42 days
Safety Issue:
Description:DLT will be defined based on the rate of drug-related grade 3-5 adverse events experienced within the first 6 weeks (2 cycles) of study treatment. These will be assessed via CTCAE version 5.0

Details

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

Last Updated

March 27, 2020