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

  • STATUS
    Recruiting
  • End date
    Dec 1, 2023
  • participants needed
    70
  • sponsor
    Ascentage Pharma Group Inc.
Updated on 28 August 2021
platelet count
measurable disease
bone marrow procedure
dexamethasone
lenalidomide
refractory multiple myeloma

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

Description

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.

Arm A: APG-2575 will be administered in combination with Pd to determine the MTD and /RP2D of APG-2575 in subjects with R/R MM.

3+3 design will be utilized in dose escalation phase of APG-2575 in combination with Pd. The starting target dose of APG-2575 is 400 mg (dose level; DL1) and will be escalated in subsequent cohorts to 600 mg (DL2), 800 mg (DL3) accordingly. Dose reduction to 200 mg (DL-1) is acceptable if APG-2575 at dose of 400 mg cannot be tolerated. This rule-based design proceeds with cohorts of three patients. If none of the three patients enrolled in DL1 experiences a DLT, another three patients will be treated at DL2, and so on. However, if one patient experiences a DLT, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience DLT. MTD is conventionally defined as the highest dose level at which 33% of patients experience DLT. Higher dose level would be considered after a comprehensive analyses of safety data in the context of 800 mg can be well tolerated, otherwise, 800 mg (DL3) should be considered as MTD (Arm A). RP2D (Arm A) will be determined based on efficacy and safety profile of APG-2575 in combination with Pd.

Patients will receive APG-2575 at target dose once daily for 28 days plus pomalidomide (4 mg ) on Days 1 through 21 and dexamethasone (40 mg for patients 75 years old or 20 mg for patients > 75 years old) on Days 1, 8, 15, and 22 of a repeated 28-day cycle

Details
Condition Multiple Myeloma, Lymphoproliferative Disorder, multiple myeloma (mm)
Treatment APG2575+ Pd, APG2575 + DRd
Clinical Study IdentifierNCT04942067
SponsorAscentage Pharma Group Inc.
Last Modified on28 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

18 years of age
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
ANC 1.0 x 109/L independent of growth factor support within 7 days of the first dose with study drug
green birefringent material in Congo red-stained tissue specimens, the type
Hemoglobin 8 g/dL without transfusion or growth factor support within 7 days of the first dose of study drug
must have been confirmed unequivocally. ii. have symptomatic organ involvement
as defined by Appendix J. Only purpura and/or carpal tunnel syndrome are not
Adequate hepatic and renal function defined as
acceptable. iii. have at least one prior line of systemic therapy for AL
AST and ALT < 3 x ULN (upper limit of normal)
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 / FLC ratio is abnormal (/ <0.26 for patients with monoclonal FLC, / >1.65 for patients with monoclonal FLC). 3. Eastern Cooperative Oncology Group (ECOG) 2. 4. Life expectancy 6 months. 5. Adequate hematologic function defined as
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)
Creatinine clearance >30mL/min(for MM patients); or Creatinine 3 mg/dL and CrCL
ml/min using the Cockcroft-Gault formula (for AL amyloidosis patients)
\. Bilirubin< 1.5 x ULN (Except if considered secondary to Gilbert's syndrome
and primarily indirect bilirubinemia)
\. PT/INR 2 x ULN and PTT (or aPTT) 2 x ULN
\. 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
\. 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
\. Ability to complete questionnaire(s) by themselves or with assistance
(For AL amyloidosis patients only)

Exclusion Criteria

Subject has previously received an allogenic stem cell transplant (regardless of timing)
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
Prior exposure to any BCL-2-directed therapy for MM
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
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
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
Subject has received antineoplastic therapy within 2 weeks before the date of registration
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
\. Subject has peripheral neuropathy grade 3
\. Subject has plasma cell leukemia (>2.0109/L circulating plasma cells by
standard differential) or Waldenstrm's macroglobulinemia or POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
changes)
\. 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)
\. Failure to have fully recovered (i.e., Grade 1 toxicity) from the
reversible effects of prior treatment for MM or AL amyloidosis
\. 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
\. 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
\. 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
\. Recent infection requiring systemic treatment that was completed14 days
before the first dose of study drug
\. Vaccinated with live, attenuated vaccines within 4 weeks of initiation of
APG2575
\. 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
\. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor
\. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
\. History of stroke or intracranial hemorrhage within 6 months prior to
enrollment
\. Any other condition or circumstance that would, in the opinion of the
investigator, make the patient unsuitable for participation in the study
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