A Study to Evaluate the Safety, Effectiveness and Tolerability of APG-2575 in Patients with Waldenström Macroglobulinemia

Overview

About this study

The purpose of this study is to assess the safety and tolerability, identify dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of APG-2575, alone or in combination with other therapeutic agents (ibrutinib or rituximab), in patients with Waldenström Macroglobulinemia (WM).

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • 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  immunoglobulin M (IgM) > 0.5g/dL), requiring treatment as per mSMART guidelines (Kyle  2003):
    • With B symptoms (fever, night sweats, fatigue, night sweats weight loss), progressive lymphadenopathy or splenomegaly, anemia (hemoglobin value of < 10 g/dL); or  
    • Platelet count <100*10^9/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  cryoglobulinemia may also be indications for therapy.
  • For Arm A only: Have received at least one prior therapy for WM. Patient must have either failed (defined as progressing while on or within 6 months of treatment with  ibrutinib treatment) or intolerant to ibrutinib.  
  • For Arm B only: Previously untreated WM.   
  • For Arm C only: Have received at least one prior therapy, relapsed or refractory WM.  
  • Adequate hematologic function defined as:  
    • ANC ≥ 1.0 x 10^9/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 10^9/L without transfusion support within 7 days of the first dose of study drug.
  • Adequate hepatic and renal function defined as:
    • AST and ALT < 2.5 x ULN (upper limit of normal);  
    • Glomerular filtration rate (GFR) > 30mL/min;  
    • Bilirubin< 1.5 x ULN.
  • PT/INR ≤ 1.5 x ULN and PTT (aPTT) ≤ 1.5 x ULN.
  • ≥ 18 years of age.  
  • Eastern Cooperative Oncology Group (ECOG) ≤ 1.
  • Life expectancy ≥ 3 months.  
  • Female subjects who are of non-reproductive potential (i.e., post-menopausal by  history-no 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 have a 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 30 days after the last dose of study drug and 90 days (males) after the last  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.
    • Clinically relevant fatigue which is not relieved by rest due to WM;
    • Symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises;
    • Lymphadenopathy which is either symptomatic or bulky (≥ 5cm in maximum diameter);
    • Symptomatic hepatomegaly and/or splenomegaly and/or organ tissue infiltration;
    • Peripheral neuropathy due to WM;
    • Symptomatic cryoglobulinemia;
    • Cold agglutinin anemia;
    • IgM related immune hemolytic anemia and/or thrombocytopenia;
    • Nephropathy related to WM;
    • Amyloidosis related to WM;
    • Hemoglobin ≤ 10g/dL;
    • Platelet count < 100 x10^9/L;
    • Serum monoclonal protein > 5g/dL, with or without overt clinical symptoms;
    • Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.  

Exclusion Criteria:

  • 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;
    • 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 14 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.
  • Any uncontrolled active systemic infection.  
  • Any concurrent malignancy.  
  • Concomitant use of warfarin or other Vitamin K antagonists (e.g., phenoprocoumon).  
  • 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 12 months prior to enrollment.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

Asher Alban Chanan Khan, M.D.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20508015

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