Rituximab and Ibrutinib (RI) Versus Dexamethasone Rituximab and Cyclophosphamide (DRC) as Initial Therapy for Waldenstr m's Macroglobulinaemia

  • STATUS
    Recruiting
  • End date
    Feb 28, 2029
  • participants needed
    148
  • sponsor
    University College, London
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Updated on 27 January 2021
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Summary

Waldenstrm's macroglobulinaemia (WM) is a rare type of slow growing lymphoma. It develops when white blood cells grow abnormally.

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 study is a phase 2-3 trial assessing 'chemotherapy free' treatment as primary therapy for 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.

In this study, 148 adults (aged 18 years) with treatment nave 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.

Details
Condition Waldenstrom's Macroglobulinemia, Waldenstrom Macroglobulinemia, Lymphoproliferative Disorder, Lymphoproliferative disorders, Lymphoproliferative disorders, Waldenstrom Macroglobulinemia
Treatment Dexamethasone, cyclophosphamide, rituximab, Rituximab, ibrutinib
Clinical Study IdentifierNCT04061512
SponsorUniversity College, London
Last Modified on27 January 2021

Eligibility

 Yes No Not Sure

Inclusion Criteria

Patients 18 years
Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein
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
No previous chemotherapy (prior plasma exchange and steroids are permissible)
Eastern Cooperative Oncology Group (ECOG) performance status grade 0 - 2
Life expectancy of greater than 6 months
Written informed consent
Willing to comply with the contraceptive requirements of the trial
Negative serum or urine pregnancy test for women of childbearing potential (WOCBP)

Exclusion Criteria

Prior therapy for WM
Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
CNS involvement with WM
Autoimmune cytopenias
Major surgery within 4 weeks prior to randomisation
Clinically significant cardiac disease including the following
Myocardial infarction within 6 months prior to randomisation
Unstable angina within 3 months prior to randomisation
New York Heart Association class III or IV congestive heart failure
History of clinically significant arrhythmias (e.g. sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
QTcF > 480 msecs based on Fredericia's formula or Bazette's formula
History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
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
Cardiac event within 6 months of screening (e.g. coronary artery stent) requiring dual antiplatelet treatment
History of stroke or intracranial haemorrhage within 6 months prior to randomisation
Requires anticoagulation with warfarin or equivalent vitamin K antagonists (direct oral anticoagulants (DOACs) allowed)
History of severe bleeding disorders considered not to be disease related (Haemophilia A, B or von Willebrand's disease)
Requires ongoing treatment with a strong CYP3A inhibitor or inducer
Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows
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
Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable
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
Renal failure (creatinine clearance <30 ml/min as estimated by the Cockroft-Gault equation)
Patients with chronic liver disease with hepatic impairment Child-Pugh class B or C
Known history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies
Inability to swallow oral medication
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)
Active systemic infection requiring treatment
Concomitant treatment with another investigational agent
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
Unwilling or unable to take PCP prophylaxis (e.g. cotrimoxazole)
History of prior malignancy, with the exception of the following
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
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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