APG-2575 Single Agent or in Combination With Ibrutinib or Rituximab in Patients With Waldenström Macroglobulinemia (MAPLE-1)

  • STATUS
    Recruiting
  • End date
    Sep 30, 2022
  • participants needed
    96
  • sponsor
    Ascentage Pharma Group Inc.
Updated on 14 March 2022
platelet count
fever
anemia
rituximab
monoclonal antibodies
measurable disease
monoclonal antibody therapy
monoclonal protein
therapeutic agents
immunoglobulin
ibrutinib
lymphadenopathy
cold agglutinin

Summary

Phase Ib/II study of safety, tolerability, efficacy and PK of APG-2575 as a single agent or in combination with other therapeutic agents including ibrutinib or rituximab.

Description

This is an open-label, multi-center Phase Ib/II study of safety, tolerability, efficacy and PK of APG-2575 as a single agent or in combination with other therapeutic agents including ibrutinib or rituximab. The study consists of the dose escalation and the dose expansion phases. The clinical trial will have multiple arms with ability to subsequently add more treatment arms based upon clinical activity of APG2575 in WM. Initially the study will contain 3 arms noted below, all the arms are independent.

Arm A: APG-2575 will be administered as a single agent to determine the MTD/RP2D in subjects who are relapsed/resistant or intolerant to ibrutinib or other BTK inhibitors.

The Dose escalation phase of APG-2575 as monotherapy will use mTPI-2 design. The starting target dose (using ramp-up if needed) is 400 mg (dose level; DL1) and will be increased to 600 mg (DL2), 800 mg (DL3) accordingly. Doses can be increased to higher level depending on safety and PK results based on discussions of the Investigators and Sponsor. APG-2575 will be administered orally once daily until time of progression or unacceptable toxicity. After the MTD/RP2D is determined, up to 12 additional patients will be enrolled at RP2D in dose-expansion phase to further evaluate safety and efficacy of APG-2575.

Arm B: APG-2575 will be administered in combination with ibrutinib in subjects with previously untreated WM.

Details
Condition Waldenstrom Macroglobulinemia
Treatment APG2575 400 mg, APG2575 600 mg, APG2575 800 mg
Clinical Study IdentifierNCT04260217
SponsorAscentage Pharma Group Inc.
Last Modified on14 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Criteria for inclusion
Patients must meet all of the following inclusion criteria to be eligible for participation
in this study
Local confirmed clinicopathological diagnosis of WM in accordance with the consensus
panel of the Second International Workshop on WM (Owen 2003)
WM patients with symptomatic and measurable disease (defined as presence of serum
For Arm B only: Previously untreated WM
immunoglobulin M (IgM)>0.5g/dL), requiring treatment as per mSMART guidelines (Kyle
For Arm C only: Have received at least one prior therapy, relapsed or refractory WM
): with B symptoms (fever, night sweats, fatigue, night sweats weight loss)
Adequate hematologic function defined as
progressive lymphadenopathy or splenomegaly, anemia (hemoglobin value of <10 g/dL) or
platelet count <100109/L due to marrow infiltration. Complications such as
hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy due to WM
systemic amyloidosis related to WM, renal insufficiency related to WM, or symptomatic
Adequate hepatic and renal function defined as
cryoglobulinemia may also be indications for therapy
AST and ALT < 2.5 x ULN (upper limit of normal)
For Arm A only: Have received at least one prior therapy for WM. Patient must have
Glomerular filtration rate (GFR) >30mL/min
either failed (defined as progressing while on or within 6 months of treatment with
Bilirubin< 1.5 x ULN
ibrutinib treatment) or intolerant to ibrutinib
ANC ≥1.0 x 109/L independent of growth factor support within 7 days of the first
dose with study drug
Hemoglobin ≥9 g/dL without transfusion or growth factor support within 7 days of
the first dose of study drug
Platelet count ≥ 75 x 109/L without transfusion support within 7 days of the
first dose of study drug
Clinically relevant fatigue which is not relieved by rest due to WM
PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN
Symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises
≥18 years of age
Eastern Cooperative Oncology Group (ECOG) ≤1
Symptomatic hepatomegaly and/or splenomegaly and/or organ tissue infiltration
Life expectancy≥3 months
Peripheral neuropathy due to WM
Female subjects who are of non-reproductive potential (i.e., post-menopausal by
Symptomatic cryoglobulinemia
history-no menses for ≥2 year; OR history of hysterectomy; OR history of bilateral
Cold agglutinin anemia
tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing
IgM related immune hemolytic anemia and/or thrombocytopenia
potential must have a negative serum pregnancy test upon study entry
Nephropathy related to WM
Male and female subjects who agree to use highly effective methods of birth control
Amyloidosis related to WM
(e.g.,condoms, implants, injectables, combined oral contraceptives, some intrauterine
devices[IUDs], sexual abstinence, or sterilized partner) during the period of therapy
Platelet count <100 x109/L
and for 30 days after the last dose of study drug and 90 days (males) after the last
Serum monoclonal protein >5g/dL, with or without overt clinical symptoms
dose of study drug
Symptomatic disease meeting at least 1 of the recommendations from the Second International
Workshop on Waldenström Macroglobulinemia for requiring treatment (Kyle 2003)
Constitutional symptoms documented in the subject's chart with supportive objective
measures, as appropriate, defined as one or more of the following disease-related
symptoms or signs
Unintentional weight loss ≥10% within the previous 6 months prior to Screening
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to Screening
without evidence of infection
Night sweats for more than 1 month prior to Screening without evidence of
infection
Lymphadenopathy which is either symptomatic or bulky (≥5cm in maximum diameter)
Hemoglobin ≤10g/dL
Any other condition or circumstance that would, in the opinion of the investigator
make the patient unsuitable for participation in the study

Exclusion Criteria

Criteria for exclusion
study
For Arm A only: Patients who have never been treated with ibrutinib
For Arm B only: Patients who have previously received any treatment for WM
For Arm C only
Patients who have previously been treated with ibrutinib or other BTK inhibitor
Any uncontrolled active systemic infection
Any concurrent malignancy
Concomitant use of warfarin or other Vitamin K antagonists (eg. phenoprocoumon)
Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor
Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
History of stroke or intracranial hemorrhage within 12 months prior to enrollment
Patients who meet any of the following exclusion criteria are not to be enrolled in this
Disease that is refractory to the last prior rituximab based-therapy defined as
either Relapse after the last rituximab-based therapy (<12 months since last dose
of rituximab), OR Failure to achieve at least a MR after the last rituximab-based
therapy
Rituximab treatment within the last 12 months before the first dose of study
drug
Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any
component of rituximab
Patients with central nervous system involvement (Bing-Neel syndrome), active
infection (including active hepatitis B or C virus infection, known human
immunodeficiency virus (HIV) positive) or any other serious (unresolved) medical
condition
Plasmapheresis <35 days prior to the initiation of study drug. (Note: Subjects with
high IgM 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 IgM value for efficacy evaluations)
Failure to have fully recovered (i.e., ≤Grade 1 toxicity) from the reversible effects
of prior treatment for WM
Significant screening electrocardiogram (ECG) abnormalities including left bundle
branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or
corrected QT interval (QTc) ≥470 msec
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
History of active or chronic infection with hepatitis C virus (HCV) or hepatitis B
virus (HBV) defined by positive polymerase chain reaction (PCR)
Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia 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
days before the first dose of APG-2575
Recent infection requiring systemic treatment that was completed≤14 days before the
first dose of study drug
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