IBRUTINIB for Waldenström macroglobulinemia

Stratification factors

• MYD88 status
• CXCR4 status
• Number of prior lines (0 vs ≥ 1)

Inclusion criteria

• {"criterion_text":"- Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM (IWWM)[66]\n- Each patient must sign an informed consent form in a fluent language of the patient indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.\n- De novo or relapsed / refractory WM independent of the genotype\n- Patients must have at least one of the following criteria to start study treatment as partly defined by consensus panel criteria from the Seventh IWWM[5\n- World Health Organization (WHO) / ECOG performance status ≤ 2.\n- Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE).\n- Age ≥ 18 years (male and female). and Life expectancy > 3 months in the opinion of the investigator.\n- adequate laboratory values\n- Women of childbearing potential (WCBP), i.e. fertile, following menarche and until becoming postmenopausal must agree to use a highly effective method of birth control for the duration of the therapy up to 6 months after end of therapy with Carfilzomib or Ibrutinib\n- Men must agree not to father a child for the duration of therapy and 6 months after and must agree to advice their female partner to use a highly effective method (use of a condom) of birth control. Males must refrain from sperm donation for the duration of treatment and at least 6 months after the last dose of Carfilzomib or Ibrutinib"}

Exclusion criteria

• {"criterion_text":"- Previous treatments with following substances: o Prior exposure to Ibrutinib or other BTK inhibitors. o Prior exposure to Carfilzomib. Prior exposure to other proteasome inhibitors is allowed if the patients were not refractory, that is, had a remission (at least minor response) duration of ≥ 6 months. Prior plasmapheresis and short-term administration of corticosteroids ≤ 6 weeks administered at a dose equivalent to ≤ 20 mg/day of prednisone is also allowed.\n- Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of Dexamethasone or equivalent dose of other corticosteroids.\n- Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e. prior radiation must have been to less than 30% of the bone marrow\n- Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs.\n- Hypersensitivity to the active substances or to any of the excipients of the investigational medicinal products.\n- Active infection within 14 days prior to randomization requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents. Such infection must be fully resolved prior to randomization.\n- Ascites requiring paracentesis within 14 days prior to randomization\n- Uncontrolled hypertension, defined as an average systolic blood pressure > 159 mmHg or diastolic > 99 mmHg despite optimal treatment (measured according European Society of Hypertension/ European Society of Cardiology [ESH / ESC] 2013 guidelines\n- History of stroke or intracranial hemorrhage within 6 months prior to randomization.\n- Known interstitial lung disease.\n- Infiltrative pulmonary disease, known pulmonary hypertension.\n- Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study.\n- Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal\n- Known severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification or at time of screening has an FEV1 of < 50% of predicted normal\n- Autologous or allogeneic stem cell transplant less than 100 days prior to randomization.\n- Vaccination with live attenuated vaccines within 30 days prior to randomization.\n- Patients who require strong or moderate inducers or inhibitors for cytochrome P450, family 3 or subfamily A (CYP3A).\n- Patients who have an uncontrolled bleeding disorder or require an anticoagulant (e.g. warfarin or other vitamin K antagonists; novel oral anticoagulants (NOACs) are allowed) at time of screening.\n- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or sponsor, if consulted, would pose a risk to patient safety or interfere with the study evaluation, procedures or completion.\n- Patient is a woman who is pregnant or breastfeeding (and do not consent to discontinue breast-feeding) or planning to become pregnant while enrolled in this study or within 6 months after the last study treatment.\n- Vulnerable patients, e.g. patients who are incapable of giving informed consent (severe dementia or psychosis, patients kept in detention).\n- Participation in another interventional clinical study within 30 days before randomization in this study\n- Active HIV, HBV or HCV infection\n- Central Nervous System involvement by lymphoma.\n- History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to randomization, other Stage 1 or 2 cancer treated with a curative intent and currently in complete remission, for ≥ 3 years\n- Uncontrolled illnesses including, but not limited to: o Uncontrolled diabetes mellitus (as indicated by metabolic derangements and / or severe diabetes mellitus related uncontrolled organ complications). o Chronic symptomatic congestive heart failure (Class NYHA III or IV) or LVEF < 40%. o Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to randomization. o Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia. o Known pericardial disease. o Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. o Cardiac amyloidosis.\n- Recent major surgery within 30 days prior to randomization.\n- Known cirrhosis (meeting child-pugh stage C).\n- Approved or investigational anticancer treatment within 21 days prior to randomization."}

Primary endpoints

• {"endpoint_text":"- Complete Remission (CR) or Very Good Partial Remission (VGPR) 12 months from randomization using the modified response criteria updated at the Sixth IWWM[1] (CR/VGPR).","definition_or_measurement_approach":"Assessed 12 months from randomization using the modified response criteria updated at the Sixth International Workshop on Waldenström's Macroglobulinemia (IWWM)."}

Secondary endpoints

• {"endpoint_text":"- Response rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 12 months","definition_or_measurement_approach":"Response rates assessed at 12 months using CR, VGPR, PR, MR and ORR (CR+VGPR+PR)."}
• {"endpoint_text":"- Response rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 24 monthsResponse rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 24 months","definition_or_measurement_approach":"Response rates assessed at 24 months using CR, VGPR, PR, MR and ORR (CR+VGPR+PR)."}
• {"endpoint_text":"- Best response","definition_or_measurement_approach":"Assessment of best overall response achieved during study treatment (per modified IWWM criteria)."}
• {"endpoint_text":"- Time to best response","definition_or_measurement_approach":"Time from randomization to the date of best response."}
• {"endpoint_text":"- Time to first response","definition_or_measurement_approach":"Time from randomization to first documented response."}
• {"endpoint_text":"- Time to treatment failure","definition_or_measurement_approach":"Time from randomization to treatment failure as defined in protocol."}
• {"endpoint_text":"- Remission Duration","definition_or_measurement_approach":"Duration of remission measured from time of remission to relapse or progression."}
• {"endpoint_text":"- Progression free survival","definition_or_measurement_approach":"Time from randomization to disease progression or death from any cause."}
• {"endpoint_text":"- Cause specific survival","definition_or_measurement_approach":"Survival specific to cause (disease-related mortality) as defined in protocol."}
• {"endpoint_text":"- Overall survival","definition_or_measurement_approach":"Time from randomization to death from any cause."}
• {"endpoint_text":"- Safety","definition_or_measurement_approach":"Assessment of adverse events, serious adverse events, and safety laboratory parameters per protocol."}
• {"endpoint_text":"- Quality of life","definition_or_measurement_approach":"Patient-reported quality of life assessments as specified in protocol."}

Austria

Earliest CTIS Part Ii Submission Date

19-09-2024

Latest Decision Or Authorization Date

14-10-2024

Processing Time Days

25

Number Of Sites

2

Number Of Participants

6

Greece

Earliest CTIS Part Ii Submission Date

25-11-2024

Latest Decision Or Authorization Date

09-01-2025

Processing Time Days

45

Number Of Sites

1

Number Of Participants

50

Germany

Earliest CTIS Part Ii Submission Date

19-09-2024

Latest Decision Or Authorization Date

09-10-2024

Processing Time Days

20

Number Of Sites

12

Number Of Participants

49

Primary sponsor

Full Name

Universitaetsklinikum Ulm AöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"Greece","full_name":"Coronis Research S.A.","duties_or_roles":"codes: 1,12","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitaetsmedizin Goettingen","duties_or_roles":"codes: 6","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitaetsklinikum Ulm AöR","duties_or_roles":"codes: 8","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Ludwig-Maximilians-Universitaet Muenchen","duties_or_roles":"codes: 10","organisation_type":"Educational Institution"}