Ensayos clínicos

Inclusion Criteria:

• Clinical and definitive histologic diagnosis of WM. Subjects must either have relapsed/refractory disease OR be treatment naïve and considered by their treating physician to be unsuitable for standard chemoimmunotherapy regimens:
  • For subjects who have received no prior therapy for WM: “Unsuitable” for treatment with a standard chemoimmunotherapy regimen must be a physician-determined status based on co-morbidities and risk factors. Physicians will need to provide and document organ system(s) and specific reason (s) for subject being considered unsuitable. Patient preference does not meet the eligibility requirement for a treatment-naïve subject to be unsuitable for treatment with a standard chemoimmunotherapy regimen.
• Meeting at least one criterion for treatment according to consensus panel criteria from the Seventh IWWM (Dimopoulos et al 2014, Table 4).
• Measurable disease, as defined by a serum IgM level > 0.5 g/dl.
• Age ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Adequate bone marrow function defined as:
  • Neutrophils ≥ 0.75 x 10^9/L, independent of growth factor support within 7 days of study entry;
  • Platelets ≥ 50 x 10^9/L, independent of growth factor support or transfusion within 7 days of study entry.
• Creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD]) based on ideal body mass.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN).
• Bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome).
• International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. Subjects with factor inhibitors that prolong PT/aPTT without increasing the bleeding risk, or those with lupus anticoagulant or acquired von Willebrand’s syndrome due to WM may be enrolled after discussion with the Medical Monitor or designee.
• Subjects who relapse after autologous stem cell transplant are eligible if they are at least 3 months after transplant and are eligible after allogeneic transplant if they are at least 6 months post-transplant. To be eligible after either type of transplant, subjects should have no active infections or, in the case of allogeneic transplant relapse, no active acute graft versus host disease (GvHD) of any grade, and no chronic GvHD other than mild skin, oral, or ocular GvHD not requiring systemic immunosuppression.
• Female subjects of childbearing potential and non-sterile males must practice highly effective methods of birth control initiated prior to first dose of study drug, for the duration of the study, and for 90 days after the last dose of study drug. These methods include the following:
  • A barrier method of contraception (including male and female condoms with or without spermicide) plus one of the following hormonal contraceptives:
    • Combined (estrogen and progestogen containing) hormonal contraception associated with the inhibition of ovulation;
    • Oral, intravaginal or transdermal;
    • Progestogen-only hormonal contraception associated with the inhibition of ovulation;
    • Oral, injectable, implantable;
    • An intrauterine device (IUD);
    • Intrauterine hormone-releasing system (IUS).
  • Bilateral tubal occlusion.
  • Vasectomized partner.
  • Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day prior to first dose of study drug, for the duration of the study, and for 90 days after the last dose of study drug).  Total sexual abstinence should only be used as a contraceptive method if it is in line with the subjects’ usual and preferred lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational medicinal product (IMP), and withdrawal are not acceptable methods of contraception.
• Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception and if used, this method must be used in combination with another acceptable method listed above. Life expectancy of > 4 months.
• Able to provide written informed consent and can understand and comply with the requirements of the study.

Exclusion Criteria:

• Prior exposure to a BTK inhibitor.
• Evidence of disease transformation at the time of study entry.
• Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy given with antineoplastic intent, targeted therapy, or radiation therapy within 4 weeks, or antibody-based therapy within 4 weeks of the start of study drug.
• Major surgery within 4 weeks of study treatment.
• Ongoing toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, absolute neutrophil count [ANC] and platelets). For ANC and platelets, please follow inclusion criteria #6 regarding neutrophils and platelets.
• History of other active malignancies within 2 years of study entry, with exception of:
  • adequately treated in-situ carcinoma of cervix; 
  • localized basal cell or squamous cell carcinoma of skin; previous malignancy confined and treated locally (surgery or other modality) with curative intent .
• Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease (congestive heart failure) as defined by the New York Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 6 months of screening.
• QTcF prolongation (defined as a QTcF > 480 msec).
• Active, clinically significant Electrocardiogram (ECG) abnormalities including second degree atrioventricular (AV) block Type II, or third-degree AV block.
• Unable to swallow capsules or disease significantly affecting gastrointestinal (GI) function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy that was completed ≤ 14 days before the first dose of study drug .
• Known infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or hepatitis C infection as follows:
  • Presence of hepatitis B surface antigen (HBsAg) or anti-hepatitis B core antibody (anti-HBc). Patients with anti-HBc, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable and if they are willing to undergo monthly monitoring for HBV reactivation;
  • Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV ribonucleic acid (RNA) is undetectable.
• Pregnant or lactating women.
• Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator’s opinion, could compromise the subject’s safety, or put the study at risk.
• Inability to comply with study procedures.
• At time of study entry, taking any medications which are strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers.
• At time of study entry, taking warfarin or other vitamin K antagonists.
• Known central nervous system (CNS) hemorrhage or stroke within 6 months prior to study entry.
• Active CNS involvement by WM. Patients with a previous history of CNS involvement must undergo magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology studies to document no evidence of CNS disease prior to study entry.
• History of intolerance to the active ingredients or other ingredients of either zanubrutinib or ibrutinib.