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

• ClinicalTrials.gov Identifier: NCT04215809
• Recruitment Status: Recruiting
• First Posted: January 2, 2020
• Last Update Posted: March 2, 2022
• Sponsor: Ascentage Pharma Group Inc.
• Information provided by (Responsible Party): Ascentage Pharma Group Inc.

Tracking Information

• First Submitted Date: December 30, 2019
• First Posted Date: January 2, 2020
• Last Update Posted Date: March 2, 2022
• Actual Study Start Date: March 2, 2020
• Estimated Primary Completion Date: December 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 30, 2019)

• Primary Toxicity Endpoint: dose limiting toxicity (DLT) [ Time Frame: 42 days ]
  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
• Maximally tolerated dose (MTD) [ Time Frame: 42 days ]
  MTD will be determined based on DLTs observed during the first 6 weeks (2 cycles) of study treatment

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The dose escalation study of APG-2575 as monotherapy will use the standard 3+3 design. APG-2575 will be taken orally, once daily starting with a ramp-up treatment and will receive the full dose starting on Day 1 of 28-Day-Cycle 1. The starting target dose of APG-2575 is 200 mg (using ramp-up) and will be increased in subsequent cohorts to 400 mg, 600 mg, 800 mg and 1200 mg accordingly.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: CLL/SLL

Intervention

Drug: APG2575

APG2575 investigation drug in ramp up dosing

Study Arms

• Experimental: APG2575 200mg
  APG2575 200mg ramp up
  Intervention: Drug: APG2575
• Experimental: APG2575 400mg
  APG2575 400mg ramp up
  Intervention: Drug: APG2575
• Experimental: APG 2575 600mg
  APG2575 600mg ramp up
  Intervention: Drug: APG2575
• Experimental: APG2575 800mg
  APG2575 800mg ramp up
  Intervention: Drug: APG2575
• Experimental: APG2575 1000 mg
  APG2575 1000 mg ramp up
  Intervention: Drug: APG2575
• Experimental: APG2575 1200mg
  APG2575 1200mg ramp up
  Intervention: Drug: APG2575

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 30, 2019): 35
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 30, 2023
• Estimated Primary Completion Date: December 30, 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Angela Kaiser; 301-509-0357; angela.kaiser@ascentage.com

• Listed Location Countries: Australia, United States
• Removed Location Countries: Georgia, Russian Federation, Ukraine

Administrative Information

• NCT Number: NCT04215809
• Other Study ID Numbers: APG2575CU101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ascentage Pharma Group Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Ascentage Pharma Group Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Ascentage Pharma Group Inc.
• Verification Date: February 2022