Relapsed or refractory Waldenstrom’s Macroglobulinemia MedDRA version: 16.1 Level: PT Classification code 10047804 Term: Waldenstrom's macroglobulinaemia recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Ibrutinib
Product Code: PCI-32765
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ibrutinib
CAS Number: 936563-96-1
Other descriptive name: PCI-32765
Concentration unit: mg milli
Sponsors
Pharmacyclics, Incorporated
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For the Randomized Study (Arm A and Arm B): - Previously treated for Waldenstrom’s macroglobulinemia and have either documented disease progression or had no response (stable disease) to the most recent treatment regimen. - Centrally confirmed clinicopathological diagnosis of WM in accordance with the consensus panel of the Second International Workshop on WM (Owen 2003). - Measurable disease defined as serum monoclonal IgM >0.5 g/dL. - Symptomatic disease meeting at least 1 of the recommendations from the Second International Workshop on Waldenström Macroglobulinemia for requiring treatment (Kyle 2003). - Adequate hematologic function. - Adequate hepatic and renal function. - PT/INR =1.5 x ULN and PTT (aPTT) =1.5 x ULN. - Eastern Cooperative Oncology Group (ECOG) performance status of =2. Ethical/Other For the Open-label Substudy Treatment Arm C: To be enrolled in the substudy, each potential subject must meet all of the inclusion criteria defined in Protocol Section 4.1.1 (Arm A & Arm B). IN ADDITION, the following criterion must be met: 1. Disease that is refractory to the last prior rituximab-containing therapy defined as either • Relapse after the last rituximab-containing therapy =65 years) yes F.1.3.1 Number of subjects for this age range 90
Exclusion criteria
Exclusion criteria: - Known involvement of the central nervous system by WM. - Disease that is refractory to the last prior rituximab-containing therapy defined as either • Relapse after the last rituximab-containing therapy <12 months since last dose of rituximab, OR • Failure to achieve at least a MR after the last rituximab-containing therapy. If the subject meets this exclusion criterion and therefore is excluded from the main randomized study, participation in the non randomized substudy (Arm C) may be considered (Section 4.2) - 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. - Prior exposure to ibrutinib or other BTK inhibitors. - Received any WM-related therapy (eg, chemotherapy, immunotherapy, investigational drug) =30 days prior to first administration of study treatment. - Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia. - History of stroke or intracranial hemorrhage within 12 months prior to enrollment. - Known history of infection with human immunodeficiency virus (HIV). - History of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) . - Any uncontrolled active systemic infection. - Major surgery (as defined in Section 6.2.2) within 4 weeks of first dose of study drug. - Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk. - Significant screening electrocardiogram (ECG) abnormalities. - Currently active, clinically significant cardiovascular disease. - Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function. - Concomitant use of warfarin or other Vitamin K antagonists. - Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor. The exclusion criteria for the substudy are identical to those of the main randomized study as described in Protocol Section 4.1.2, EXCEPT for criteria 2, 3, and 4, which are related to prior rituximab use and do not apply for the substudy Arm C.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of the addition of ibrutinib to rituximab on progression-free survival (PFS) assessed by an independent review committee (IRC) in subjects with previously treated Waldenstrom’s Macroglobulinemia WM. Efficacy evaluations will be based on the modified Consensus Response Criteria from the VIth International Workshop for WM (NCCN 2014).;Secondary Objective: Efficacy To compare the treatment arms in terms of the following: • Overall Response Rate (ORR) assessed by IRC (= PR; according to the modified VIth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) [NCCN 2014] criteria). • Hematological improvement measured by hemoglobin. • Time to next treatment (TTnT).Overall survival (OS). Safety • To evaluate the safety and tolerability of ibrutinib when combined with rituximab therapy compared to rituximab in combination with placebo.;Primary end point(s): Progression-free survival (PFS) assessed by an independent review committee (IRC), which is defined as duration from the date of randomization to the date of disease progression or death, whichever is first reported, assessed according to the modified VIth IWWM (NCCN 2014) criteria. ;Timepoint(s) of evaluation of this end point: Refer to protocol section 10.6.1. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Multiplicity adjustment will be made in a sequential hierarchical manner based on a closed testing procedure as outlined in protocol section 10.8 (interim analysis) to control the overall type 1 error. - Overall response rate (ORR) defined as the proportion of subjects who achieve Partial response (PR) or better according to the modified VIth IWWM (NCCN 2014) criteria as assessed by IRC. - Hematological improvement as measured by change from baseline hemoglobin level. - Time-to-next treatment (TTnT) as measured from the date of randomization to the start date of any subsequent WM treatment. - Overall survival (OS) as measured from the date of randomization to the date of the subject’s death from any cause.;Timepoint(s) of evaluation of this end point: Refer to protocol section 10.6.2. | — |
Countries
Australia, Canada, Germany, Greece, Italy, Spain, United Kingdom, United States
Contacts
Public ContactMedical Monitor
Pharmacyclics, Incorporated
Outcome results
None listed