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CLL210   

Title

Phase II trial of ofatumumab, dexamethasone and lenalidomide for high-risk CLL (NCRI CLL210)


Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs
II Treatment Closed RLBUHT and UoL Eudract No: 2010-019575-29
Isrctn No: ISRCTN40303610

Purpose

CLL210 is a new phase II trial of ofatumumab, dexamethasone and lenalidomide for patients with high-risk CLL, defined as 17p- or early failure of fludarabine. Patients who respond to induction treatment and do not have an allogeneic transplant are randomised to lenalidomide maintenance versus no further treatment.

Rituximab containing chemo-immunotherapy has been shown to be ineffective in treating high risk CLL, and improving outcomes for affected patients is an important area of unmet clinical need.

A previous phase II study (CLL206) demonstrated that alemtuzumab-glucocorticoid combination therapy is effective in 17p- CLL, but improvement could be made in terms of response rates and toxicity. CLL210 will evaluate a new induction regimen that differs from CLL206 in three main respects:

- A third drug (lenalidomide - an oral agent with established activity in high-risk CLL) is included.

- The glucocorticoid regimen has been changed to pulsed oral dexamethasone, which contains a lower glucocorticoid dose than used in CLL206.

- Alemtuzumab is replaced by an alternative monoclonal antibody, ofatumumab.

CLL210 originally used dexamethasone, lenalidomide and alemtuzumab in combination. In August 2012, Sanofi withdrew the licence for alemtuzumab as it was planned to market it for other indications. Because of difficulties in obtaining alemtuzumab suitable for trial use recruitment was suspended on 11 September 2012. Because of doubts about alemtuzumab's long term use in CLL, a decision was made to re-launch the study with alemtuzumab replaced by ofatumumab, an alternative monoclonal antibody. It is believed that ofatumumab will be as efficacious as alemtuzumab with reduced toxicity.


Trial Start Date

23/01/2012


Trial Coordinator

Matthew Bickerstaff


Trial Coordinator Email Address

oasis@liverpool.ac.uk


Trial Coordinator Contact No

0151 794 8934


Website Treatment  

All patients receive 24 weeks of induction treatment consisting of:
- 40mg oral dexamethasone, days 1-4, weeks 1,3,5,7,8,11,13 & 15
- 5mg oral lenalidomide daily weeks 3-4, 10mg oral lenalidomide daily weeks 5-24
- 1000mg intravenous ofatumumab (300mg week 7) day 1 weeks 7-15, 17, 19, 21

Patients who achieve a CR or PR at 24 weeks may elect to receive an allogeneic stem-cell transplant.

Those responders who decide not to have a transplant will be randomised between receiving lenalidomide maintenance until disease progression or receiving no further trial treatment.

Trial Endpoints  

The CLL210 trial will investigate the safety and efficacy of combination induction therapy with ofatumumab,dexamethasone and lenalidomide in patients with high risk CLL.

In addition the trial will also examine the value of continuing lenalidomide as post-induction maintenance for patients who achieve a CR or PR.


Primary Outcome  


- Complete Response after 6 months of induction therapy
- Progression free rate after 2 years of maintenance therapy.


Secondary Outcomes  


- Toxicity
- Overall, complete and partial response rates
- Minimum Residual Disease (MRD) negativity rate
- MRD-negative CR rate
- Overall survival
- Progression-free survival (progression or death)
- Event-free survival (progression, death or further induction treatment)
- Response duration
- Quality of life
- Cumulative dose of individual drugs administered

Eligibility  

Main Inclusion Criteria are:

- CLL/SLL requiring treatment by IWCLL 2008 criteria. At least one of the following criteria should be met:
o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia
o Massive (i.e. at least 6cm below the left costal margin) or progressive or symptomatic splenomegaly
o Massive (i.e. at least 10cm in longest diameter) or progressive or symptomatic lymphadenopathy
o Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months from a baseline value of at least 30x10^9/l and not due to causes other than CLL.
o Constitutional symptoms defined as at least 10% unintentional weight loss within the previous 6 months, significant fatigue preventing usual activities, or fever of at least 38°C for at least 2 weeks or night sweats for at least one month in the absence of infection.

- High risk CLL/SLL defined by at least one of the following criteria:
o TP53 deletion or mutation affecting at least 20% of CLL cells
o Resistant (SD/PD) to fludarabine-containing combination therapy
o Relapse within 12 months of responding to fludarabine-containing combination therapy

- No prior treatment with alemtuzumab or lenalidomide

- CLL not known to be resistant to glucocorticoids

- No more than 3 previous treatment episodes for CLL

- WHO performance status 0-2

- Aged at least 18 years

- Written Informed Consent


Main Exclusion Criteria are:

- Neutrophil count less than 0.5x10^9/l or platelet count less than 25x109/l

- Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia

- Total bilirubin >1.5 times upper normal limit (unless due to involvement of liver or a known history of Gilbert's disease) or ALT >2.5 times upper normal limit (unless due to disease involvement of liver)

- Active infection

- Active gastritis or peptic ulcer disease

- Uncontrolled diabetes mellitus or hypertension

- History of recurrent thromboembolism

- Seropositivity for HIV, HCV or HBV (surface antigen or core antibody)

- Renal impairment (glomerular filtration rate less than 30ml/min as measured by 24 hour urine collection for creatinine clearance or EDTA scan)

- Hepatic impairment (serum bilirubin more than twice the upper limit of normal)

- Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg od

- Presence or history of CNS disease (either CNS lymphoma or leukaemic meningitis)

- History of Richter transformation

- Concomitant malignancies except adequately treated localised non-melanoma skin cancers and other in-situ cancers, or invasive cancers that have been in remission for a period of time considered by the local investigator to pose a negligible risk of relapse during the period of the trial.

- Major surgery within 28 days prior to registration

- Any serious underlying medical or psychological conditions, which could impair the ability of the patient to participate in the trial or compromise ability to give informed consent

- Treatment within a clinical trial within 30 days prior to trial entry

- Adult patient under tutelage (not competent to sign informed consent)
- Pregnant or lactating women

- Patients unwilling or not able to adhere to the Lenalidomide Pregnancy Prevention Plan Women taking the oral contraceptive pill within 4 weeks of study registration owing to an increased risk of thromboembolism

- Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy


UK: ENGLAND

  • Birmingham, Heartlands Hospital (Birmingham) (Don Milligan)
  • Bournemouth, The Royal Bournemouth Hospital (Helen McCarthy)
  • Cottingham, Castle Hill Hospital (Cottingham) (David Allsup)
  • Eastbourne, Eastbourne District General Hospital (Sunil Gupta)
  • Gateshead, Queen Elizabeth Hospital (Gateshead) (Scott Marshall)
  • Leeds, St. James's University Hospital (Leeds) (Peter Hillmen)
  • Leicester, Leicester Royal Infirmary (Ben Kennedy)
  • Liverpool, Royal Liverpool University Hospital (Andrew Pettitt)
  • London, King's College Hospital (London) (Stephen Devereux)
  • London, University College Hospital (London) (Amit Nathwani)
  • Manchester, The Christie (Manchester) (Adrian Bloor)
  • Nottingham, Nottingham City Hospital (Christopher Fox)
  • Oxford, Churchill Hospital (Oxford) (Anna Schuh)
  • Plymouth, Derriford Hospital (Plymouth) (Simon Rule)
  • Southampton, Southampton General Hospital (Andrew Duncombe)
  • Sutton, Royal Marsden Hospital (Sutton) (Claire Dearden)

UK: SCOTLAND

  • Aberdeen, Aberdeen Royal Infirmary (Gavin Preston)
  • Glasgow, The Beatson West of Scotland Cancer Centre (Glasgow) (Alison McCaig)

UK: WALES

  • Bangor, Ysbyty Gwynedd (Bangor) (James Seale)
  • Bodelwydden, Glan Clwyd Hospital (Rhyl) (Earnest Heartin)
  • Cardiff, University Hospital of Wales (Christopher Fegan)

UK: ENGLAND

  • Bristol, Bristol Haematology and Oncology Centre (Rachel Protheroe)
  • Cambridge, Addenbrooke's Hospital (Cambridge) (George Follows)
  • Canterbury, Kent and Canterbury Hospital (Christopher Pocock)
  • Gloucester, Gloucestershire Royal Hospital (Gloucester) (Rebecca Frewin)
  • London, St. Bartholomew's Hospital (London) (Samir Agrawal)
  • Manchester, Manchester Royal Infirmary (Sarah Burns)
  • Newcastle upon Tyne, Royal Victoria Infirmary (Newcastle) (Jonathan Wallis)
  • Reading, Royal Berkshire Hospital (Reading) (Henri Grech)
  • Torquay, Torbay Hospital (Torquay) (Deborah Turner)
  • Truro, Royal Cornwall Hospital (Truro) (Julie Blundell)
  • Wolverhampton, New Cross Hospital (Wolverhampton) (Abraham Jacob)

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Frequently Asked Questions  

A list of FAQ's will appear here soon. If you have any questions please contact the CLL210 Trial Coordinator.