| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Waldenström's macroglobulinaemia |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase II: to assess the preliminary efficacy (response) of the ‘chemotherapy free’ combination of rituximab and ibrutinib (RI) as primary therapy for WM.
Phase III: to assess whether PFS is improved with rituximab/ibrutinib (RI) when compared to dexamethasone/rituximab/cyclophosphamide (DRC).
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| E.2.2 | Secondary objectives of the trial |
•To determine the safety and tolerability of the experimental (RI) arm compared to the control arm (DRC)
•To determine the overall response rate to RI and DRC (at end of randomised treatment and best response over any time point)
•To determine the time to best response and time to next therapy of the two arms
•To assess the depth of response and duration of response of RI compared to DRC
•To determine the overall survival of patients treated with RI compared to DRC
•To determine the effect of RI and DRC on quality of life |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients ≥18 years
2.Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein
3.Previously untreated disease at any stage requiring therapy at the discretion of the treating physician. Suggested criteria for initiating treatment include:
- haematological suppression to Hb <10g/dl, or neutrophils <1.5x109/l or platelets <150x109/l
- clinical evidence of hyperviscosity
- bulky lymphadenopathy and/or bulky splenomegaly
- presence of B symptoms
4.No previous chemotherapy (prior plasma exchange and steroids are permissible)
5.Eastern Cooperative Oncology Group (ECOG) performance status grade 0 – 2
6.Life expectancy of greater than 6 months
7.Written informed consent
8.Willing to comply with the contraceptive requirements of the trial
9.Negative serum or urine pregnancy test for women of childbearing potential (WOCBP) |
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| E.4 | Principal exclusion criteria |
1. Prior therapy for WM
2. Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
3. CNS involvement with WM
4. Autoimmune cytopenias
5. Major surgery within 4 weeks prior to randomisation
6. Clinically significant cardiac disease including the following:
o Myocardial infarction within 6 months prior to randomisation
o Unstable angina within 3 months prior to randomisation
o New York Heart Association class III or IV congestive heart failure
o History of clinically significant arrhythmias (e.g. sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
o QTcF > 480 msecs based on Fredericia’s formula
o History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
o Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mm Hg
o Cardiac event within 6 months of screening (e.g. coronary artery stent) requiring dual antiplatelet treatment
7. History of stroke or intracranial haemorrhage within 6 months prior to randomisation
8. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (direct oral anticoagulants (DOACs) allowed)
9. History of severe bleeding disorders considered not to be disease related (Haemophilia A, B or von Willebrand’s disease)
10. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
11. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:
o Presence of hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the patient will be excluded
o Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable
12. Women who are pregnant or breastfeeding or males expecting to conceive or father children at any point from the start of treatment until the end of the “at risk period"
13. Renal failure (creatinine clearance <30 ml/min as estimated by the Cockroft-Gault equation)
14. Patients with chronic liver disease with hepatic impairment Child-Pugh class B or C
15. Known history of anaphylaxis to any of the IMPs or its excipients, in addition to murine derived monoclonal antibodies
16. Received live vaccine six weeks prior to first dose of study therapy
17. Inability to swallow oral medication
18. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (e.g. malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease)
19. Active systemic infection requiring treatment
20. Concomitant treatment with another investigational agent
21. 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 patient’s safety, or put the study at risk
22. Unwilling or unable to take PJP prophylaxis (e.g. cotrimoxazole)
23. History of prior malignancy, with the exception of the following:
o Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
o Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma, superficial bladder cancer, carcinoma in situ of the cervix or breast or localized Gleason score 6 prostate cancer without current evidence of disease.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase II: to assess the preliminary efficacy (response) of the ‘chemotherapy free’ combination of rituximab and ibrutinib (RI) as primary therapy for WM.
Phase III: to assess whether PFS is improved with rituximab/ibrutinib (RI) when compared to dexamethasone/rituximab/cyclophosphamide (DRC).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase II: The primary endpoint is the overall response rate at week 24. This analysis will be performed on the first 45 eligible RI patients and presented as a proportion and 80% confidence interval. Patients who progress or die during the first 6 cycles will be counted as non-responders
Phase III: The primary endpoint is PFS. Kaplan Meier survival analysis, Cox regression and the log rank test will be used to analyse this endpoint. Time will be measured from the date of randomisation until progression or death from any cause (whichever comes first), patients alive and progression free will be censored at the date last seen. The analysis of the primary endpoint is planned for 2 years after the last randomisation. Further information in the protocol |
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| E.5.2 | Secondary end point(s) |
- To determine the safety and tolerability of RI compared to DRC
- To determine the ORR to RI compared to DRC (at end of randomised treatment and best response over any time point)
- To determine the time to best response and time to next therapy of the two arms
- To assess the depth of response and duration of response of RI compared to DRC
- To determine the overall survival of patients treated with RI compared to DRC
- To determine the effect of RI and DRC on quality of life
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 50 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| the end of the trial will be 5 years after the last patient has completed RI/DRC randomised treatment |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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