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Trial Details
Trial status:
Active (recruiting)
Recruitment start date:
03/02/2020
Funder:
Sponsor:
UCL
Chief Investigator:
Rebecca Auer
Recruitment target:
148
EudraCT number:
2019-001261-33
Contact details:
ctc.rainbow@ucl.ac.uk
Lay summary:
RAINBOW
Randomised phase II/III study of Rituximab and Ibrutinib (RI) versus Dexamethasone, Rituximab and Cyclophosphamide (DRC) as initial therapy for Waldenström’s macroglobulinaemia
Description
Design:
The RAINBOW study is a phase 2-3 trial assessing ‘chemotherapy free’ treatment as primary therapy for Waldenström’s macroglobulinaemia (WM) which can potentially improve response outcome, durability and importantly, reduce toxicity for WM patients. This approach will be done using the drug Ibrutinib, which in combination with rituximab (RI) will be the experimental arm. As there is no agreed standard on first-line therapy for WM, the control arm is the current treatment based on the most recently published clinical trial results. The control arm consists of rituximab, cyclophosphamide and dexamethasone (DCR), and is widely recommended by international consensus as appropriate treatment for first-line therapy for WM.

Treatment:
In this study, 148 adults (aged ≥ 18 years) with treatment naïve WM will be randomised on a 1:1 ratio to either the treatment or control arm. Randomised treatment lasts for a maximum of 6 cycles and response will be assessed following 3 cycles of treatment and completion of randomised treatment at approximately 24 weeks after commencing treatment. RI patients may then have up to 5 years of Ibrutinib monotherapy. Patients will be seen regularly during treatment and then every 3 months for 5 years after treatment discontinuation. Patients will enter annual follow up for survival until the end of trial (including progressed patients).

The study will be conducted at NHS hospitals and is expected to last 9 years and 6 months.
Key inclusion/exclusion criteria:
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:

a) haematological suppression to Hb
b) clinical evidence of hyperviscosity
c) bulky lymphadenopathy and/or bulky splenomegaly
d) 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)


Exclusion criteria

1. Priortherapy for WM

2. Lymphoplasmacyticlymphoma with no detectable serum IgM paraprotein

3.   CNSinvolvement with WM

4.   Autoimmunecytopenias

5.   Majorsurgery within 4 weeks prior to randomisation

6.   Clinicallysignificant cardiac disease including the following:

o  Myocardialinfarction within 6 months prior to randomisation

o  Unstableangina within 3 months prior to randomisation

o  NewYork Heart Association class III or IV congestive heart failure

o  Historyof clinically significant arrhythmias (e.g. sustained ventricular tachycardia,ventricular fibrillation, torsades de pointes)

o  QTcF> 480 msecs based on Fredericia’s formula

o  Historyof Mobitz II second degree or third degree heart block without a permanentpacemaker in place

o  Uncontrolledhypertension as indicated by a minimum of 2 consecutive blood pressuremeasurements showing systolic blood pressure > 170 mmHg and diastolic bloodpressure > 105 mm Hg

o  Cardiacevent within 6 months of screening (e.g. coronary artery stent) requiring dualantiplatelet treatment

7.   Historyof stroke or intracranial haemorrhage within 6 months prior to randomisation

8.   Requiresanticoagulation with warfarin or equivalent vitamin K antagonists (direct oralanticoagulants (DOACs) allowed)

9.   Historyof severe bleeding disorders considered not to be disease related (HaemophiliaA, B or von Willebrand’s disease)

10. Requires ongoing treatment with a strongCYP3A inhibitor or inducer

11. Known infection with HIV, or serologicstatus reflecting active hepatitis B or C infection as follows:

o  Presenceof hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg butHBcAb positive (regardless of HBsAb status), a HB DNA test will be performedand if positive the patient will be excluded

o  Presenceof hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody areeligible if HCV RNA is undetectable

12. Women who are pregnant or breastfeedingor males expecting to conceive or father children at any point from the startof treatment until the end of the “at risk period” – see section 12.7 fordetails

13. Renal failure (creatinine clearance

14. Patients with chronic liver disease withhepatic impairment Child-Pugh class B or C

15. Known history of anaphylaxis to any ofthe IMPs or its excipients, in addition to murine derived monoclonalantibodies.

16. Received live vaccine six weeks prior tofirst dose of study therapy

17. Inability to swallow oral medication

18. Disease significantly affectinggastrointestinal function and/or inhibiting small intestine absorption (e.g. malabsorptionsyndrome, resection of the small bowel, poorly controlled inflammatory boweldisease)

19. Active systemic infection requiringtreatment

20. Concomitant treatment with anotherinvestigational agent

21. Any life-threatening illness, medicalcondition, organ system dysfunction, need for profound anticoagulation, orbleeding disorder, which, in the investigator’s opinion, could compromise the patient’ssafety, or put the study at risk

22. Unwilling or unable to take PJP prophylaxis(e.g. cotrimoxazole)

23. History of prior malignancy, with theexception of the following:


o  Malignancytreated with curative intent and with no evidence of active disease present formore than 3 years prior to screening and felt to be at low risk for recurrenceby treating physician 


o  Adequately treated non-melanomatous skin cancer or lentigomaligna melanoma, superficial bladder cancer, carcinoma in situ of the cervixor breast or localized Gleason score 6 prostate cancer without current evidenceof disease. 

Duration of recruitment: 4 years
Aim
Typically a disease of the elderly, the median age of presentation is >70 years and the current treatment for WM is unsatisfactory, with incomplete responses and inevitable recurrence. Therefore there is a need to find alternative treatments that are more effective, leading to lasting responses and improved quality of life. The RAINBOW trial investigates the safety and response of the 'chemotherapy free' RI combination as primary therapy for WM.
Trial protocols
Trial protocols must not be applied to patients treated outside trials. UCL CTC can only ensure that approved trial investigators are provided with amendments to protocols.
No protocols have been currently made available for download
Trial documents
No documents have been currently made available for download
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