APG-2575 in Combination With Novel Therapeutic Regimens in Subjects With Relapsed or Refractory Multiple Myeloma

• Status: Recruiting
• Trial end date: 2023-12-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase Ib/II, open-label, multi-center study evaluating the safety, tolerability, efficacy, and PK/ Pharmacodynamics of APG-2575 in combination with Pd/DRd in patients with relapsed/refractory (RR) multiple myeloma (MM). The study consists of dose escalation and dose expansion phases. The study consists of will start with 2 arms noted below, both arms are independent

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Ascentage Pharma Group Inc.
• Treatments: BB 1101; Daratumumab; Dexamethasone; Dexamethasone acetate; Lenalidomide; Pomalidomide

Criteria

Inclusion Criteria:

1. ≥ 18 years of age.

2. MM patients (for Arm A and Arm B): Patients with Relapsed/Refractory MM per 2016 IMWG criteria, previously treated with at least 1 but not more than 4 prior lines of therapy for MM. Refractory MM, meanwhile, is defined as disease that progresses on salvage therapy or progresses within 60 days of the last treatment.

AL amyloidosis patients (for Arm C ONLY): Patients with AL amyloidosis when meeting:

i. histochemical diagnosis based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, the type must have been confirmed unequivocally. ii. have symptomatic organ involvement as defined by Appendix J. Only purpura and/or carpal tunnel syndrome are not acceptable. iii. have at least one prior line of systemic therapy for AL. Patients who do not achieve at least a PR to frontline therapy in 3 months are eligible. iv. have measurable disease as defined by at least ONE of the following:

• Serum monoclonal protein ≥1.0 g/dl by protein electrophoresis.

• >200 mg of monoclonal protein in the urine on 24-hour electrophoresis.

• Serum differential FLC concentration (dFLC, difference between amyloid forming [involved] and nonamyloid forming [uninvolved] free light chain [FLC]) > 5 mg/dL; OR serum FLC of 7.5 mg/dL provided the κ/λ FLC ratio is abnormal (κ/λ <0.26 for patients with monoclonal λ FLC, κ/λ >1.65 for patients with monoclonal κ FLC).

3. Eastern Cooperative Oncology Group (ECOG) ≤ 2.

4. Life expectancy ≥ 6 months.

5. Adequate hematologic function defined as:

1. ANC ≥1.0 x 109/L independent of growth factor support within 7 days of the first dose with study drug.

2. Hemoglobin ≥8 g/dL without transfusion or growth factor support within 7 days of the first dose of study drug.

3. Platelet count ≥ 50 x 109/L without transfusion support within 7 days of the first doseof study drug (for MM patients); or platelet count ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement independent of transfusion support in either (for AL amyloidosis patients).

6. Adequate hepatic and renal function defined as:

1. AST and ALT < 3 x ULN (upper limit of normal)

2. Creatinine clearance >30mL/min(for MM patients); or Creatinine ≤3 mg/dL and CrCL

≥25 ml/min using the Cockcroft-Gault formula (for AL amyloidosis patients)

3. Bilirubin< 1.5 x ULN (Except if considered secondary to Gilbert's syndrome and primarily indirect bilirubinemia)

7. PT/INR ≤2 x ULN and PTT (or aPTT) ≤2 x ULN.

8. Female subjects who are of non-reproductive potential (i.e., post-menopausal by historyno menses for ≥2 year; OR history of hysterectomy; OR history of bilateral tubal ligation;OR history of bilateral oophorectomy). Female subjects of childbearing potential must havea negative serum pregnancy test upon study entry.

9. Male and female subjects who agree to use highly effective methods of birth control (e.g.,condoms, implants, injectables, combined oral contraceptives, some intrauterine devices[IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 90days after the last dose of study drug.

10. Ability to complete questionnaire(s) by themselves or with assistance (For AL amyloidosis patients only).

Exclusion Criteria:

1. MM patients with newly diagnosed MM, previously untreated for MM or only had been treated with localized palliative treatment or steroids less than equivalent of dexamethasone 40 mg daily for 4 days). AL amyloidosis patients with AL amyloidosis have not been treated with any systemic therapy, or AL amyloidosis clinically overt multiple myeloma i.e. original CRAB criteria. Extent of marrow plasmacytosis is not prohibitive.

2. Subject has received antineoplastic therapy within 2 weeks before the date of registration.

3. Subject has previously received an allogenic stem cell transplant (regardless of timing).

4. Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, i.e., these subjects should not be enrolled in order to reduce disease burden prior to transplant.

5. Prior exposure to any BCL-2-directed therapy for MM.

6. For Arm A only: The subjects show evidence of intolerance to pomalidomide, which is defined as subjects discontinued due to any AEs related to prior pomalidomide treatment;

7. For Arm B only: The subjects show evidence of intolerance to daratumumab or lenalidomide, which is defined as subjects discontinued due to any AEs related to prior daratumumab or lenalidomide treatment;

8. Patients with any uncontrolled active systemic infection, including but not limited to :

active hepatitis B or C virus infection, known human immunodeficiency virus (HIV) positive

9. Subject has peripheral neuropathy ≥grade 3.

10. Subject has plasma cell leukemia (>2.0*109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).

11. Plasmapheresis <35 days prior to the initiation of study drug. (Note: Subjects with high Mprotein values or hyper-viscosity symptoms during screening may receive plasmapheresis prior to initiating study drug if the previous plasmapheresis was performed >35 days before the plasmapheresis performed during screening (in order to obtain a true baseline M-protein value for efficacy evaluations).

12. Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior treatment for MM or AL amyloidosis..

13. Unable to swallow tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

14. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia (including Frederica corrected QT interval (QTc) ≥470 msec ) or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.

15. Major surgical procedure within ≤14 days prior to initiating study treatment, or anticipation of the need for major surgery during the course of the study treatment, radiotherapy ≤14 days prior to initiating study treatment, systemic treatment within 14 days before the first dose of APG2575.

16. Recent infection requiring systemic treatment that was completed≤14 days before the first dose of study drug.

17. Vaccinated with live, attenuated vaccines within 4 weeks of initiation of APG2575.

18. Subject has any concurrent or recent malignancy ≤ 1 year prior to registration with the exception of: basal or squamous cell skin cancer, any carcinoma in situ,. NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.

19. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

20. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.

21. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

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