Clinical trial NCT01592981: Randomised Trial in Waldenstrom's Macroglobulinaemia
Official title: Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of Waldenstrőm's Macroglobulinaemia (WM): a Randomized Phase II Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Waldenstrom's Macroglobulinaemia
Keywords: Waldenstrom's macroglobulinaemia
bortezomib
cyclophosphamide
rituximab
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2012-05-07
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to assess tolerability and efficacy of the Bortezomib, Cyclophosphamide and Rituximab combination as initial therapy for previously untreated patients with symptomatic Waldenstrom's macroglobulinaemia.

Detailed description: Waldenstrom macroglobulinaemia (WM) is a low grade nonHodgkin lymphoma characterised by bone marrow infiltration and the presence of an abnormal protein in the blood (IgM paraprotein. Most patients require treatment at presentation but there is no agreed standard of first line therapy. Current treatment is unsatisfactory with responses often incomplete and slow to attain, while recurrence is inevitable.

The aim of this study is to find out whether a new combination of Bortezomib (Velcade®), Cyclophosphamide and Rituximab (MabThera), is well tolerated and effective for patients with WM. R2W is a randomised, noncomparative, phase II trial of subcutaneous bortezomib, cyclophosphamide, rituximab (BCR, experimental arm) versus fludarabine, cyclophosphamide, rituximab (FCR, control arm) for initial therapy of WM. This is a two stage trial where six patients will be treated initially with BCR to assess tolerability. If BCR is considered tolerable, a further 50 patients will be randomised between BCR and FCR (2:1) in the second stage of the trial. Patients will receive 3 cycles of treatment and then be reassessed. Those with evidence of progression will stop trial treatment. All other patients will continue with a further 3 cycles (to a total of 6) unless there is a clear clinical contraindication to further treatment.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 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 \<10 g/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)
* Performance status grade 0 - 2
* Life expectancy of greater than 6 months
* Informed consent
* Agreed compliance with recommended contraceptive precautions where appropriate

Exclusion Criteria:

* Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
* Severe pre-existing neuropathy (\> grade 2)
* Autoimmune cytopenias
* Evidence of active Hepatitis B or C infection (patients with evidence of past HepB infection may be eligible - see appendix 6)
* Serological positivity for HIV
* Pregnant or lactating women
* Life expectancy severely limited by other illness
* Renal failure (creatinine clearance \<30 ml/min)
* Severe impairment of liver function: alkaline phosphatase/bilirubin \>2.5 times upper limit of normal (ULN), ALT/AST \>2.5 times ULN not related to lymphoma (patients with Gilbert syndrome are eligible)
* History of allergic reaction to compounds containing boron or mannitol
* Known hypersensitivity to murine compounds.
* Diagnosed or treated for a malignancy other than WM within 5 years before day 1 of Cycle 1 with the exception of complete resection of basal cell carcinoma, squamous cell carcinoma of the skin or any other in situ malignancy
* Active systemic infection requiring treatment
* Concurrent treatment with another investigational agent
* Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic disease

Primary outcomes:
measure: Disease response
timeFrame: 6 months (end of treatment)
Secondary outcomes:
measure: Toxicity of grade 3 or higher adverse event
timeFrame: Up to 6 months after treatment start
measure: Progression free survival
timeFrame: up to 5 years after treatment start
measure: Overall survival
timeFrame: up to 5 years after treatment start
measure: Quality of life (EQ-5D score)
timeFrame: at 3 and 6 months after treatment start
Other outcomes:
Locations:
city: Basingstoke
country: United Kingdom
facility: Basingstoke & North Hampshire Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Birmingham
country: United Kingdom
facility: City Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
city: Dewsbury
country: United Kingdom
facility: Dewsbury and District Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Grantham
country: United Kingdom
facility: Grantham and District Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: St Bartolomew's Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Northwick Park Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Pontefract
country: United Kingdom
facility: Pontefract Hospital
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
city: Torquay
country: United Kingdom
facility: Torbay Hospital
city: Tunbridge Wells
country: United Kingdom
facility: Tunbridge Wells Hospital
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital
city: West Bromwich
country: United Kingdom
facility: Sandwell Hospital
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
Study officials:
affiliation: St. Bartholomew's Hospital
name: Rebecca Auer
role: PRINCIPAL_INVESTIGATOR
References: