A Trial Looking at Ofatumumab for People With Chronic Lymphocytic Leukaemia Who Cannot Have More Intensive Treatment (RIAltO)

A Randomised Investigation of Alternative Ofatumumab-containing Regimens in Less Fit Patients With CLL

The purpose of this study is to compare ofatumumab & chlorambucil (O-Chl) versus ofatumumab & bendamustine (O-B) in patients with Chronic Lymphocytic Leukaemia who are considered not fit enough for rituximab, fludarabine & cyclophosphamide (R-FC).

Study Overview

• Status: Unknown
• Conditions: Chronic Lymphocytic Leukaemia
• Intervention / Treatment: Drug: Bendamustine; Drug: Chlorambucil; Drug: Ofatumumab

Detailed Description

Chlorambucil (Chl) has been the mainstay of CLL treatment for half a century. However, frontline treatment has improved considerably over the last decade, first by the advent of fludarabine plus cyclophosphamide (FC), and more recently by the addition of the anti-CD20 antibody, rituximab, to FC. Although FC-based regimens are considerably more effective than Chl, they are also associated with greater toxicity which makes them inappropriate for less fit patients. This is an important consideration, given that CLL predominantly affects older people who tend to have more co-morbidity. Although a single-arm phase II study (Roche MO20927; NCRI CLL208) has shown that R-Chl is safe and effective, there are no phase III data proving the benefit of adding an anti-CD20 antibody to Chl. This question is currently being addressed by a phase III RCT of Chl with or without ofatumumab (GSK OMB110911 / COMPLEMENT-1 / NCRI CLL7). Ofatumumab is a fully human anti-CD20 antibody that binds to an epitope distinct from that of rituximab and produces more complement-dependent cytotoxicity. The RIAltO trial is a direct follow-on to the NCRI CLL7 phase III RCT trial in less fit patients and therefore the Ofatumumab dose has been selected to mirror the regimen used in that trial.

• Study Type: Interventional
• Enrollment (Anticipated): 670
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kathryn Marley; Phone Number: +44 151 895 5287; Email: kathryn.marley@liv.ac.uk

Study Locations

• United Kingdom
  • Liverpool, United Kingdom
    • Recruiting
    • Royal Liverpool Hospital
    • Principal Investigator: Andrew Pettitt
  • Cheshire
    • Chester, Cheshire, United Kingdom
      • Recruiting
      • Countess of Chester Hospital
      • Principal Investigator: Salaheddin Tueger
  • Devon
    • Plymouth, Devon, United Kingdom
      • Recruiting
      • Derriford Hospital
    • Torquay, Devon, United Kingdom
      • Recruiting
      • Torbay Hospital
      • Principal Investigator: Deborah Turner
  • Dorset
    • Bournemouth, Dorset, United Kingdom
      • Recruiting
      • Royal Bournemouth Hospital
    • Dorchester, Dorset, United Kingdom
      • Recruiting
      • Dorset County Hospital
      • Principal Investigator: Akeel Moosa
  • Essex
    • Colchester, Essex, United Kingdom
      • Recruiting
      • Colchester General Hospital
      • Principal Investigator: Mike Hamblin
  • Hampshire
    • Basingstoke, Hampshire, United Kingdom
      • Recruiting
      • Basingstoke and North Hampshire Hospital
      • Principal Investigator: Sylwia Simpson
    • Southampton, Hampshire, United Kingdom
      • Recruiting
      • Southampton General Hospital
      • Principal Investigator: Andrew Duncombe
  • Hertfordshire
    • Enfield, Hertfordshire, United Kingdom
      • Recruiting
      • Barnet and Chase Farm Hospitals
      • Principal Investigator: Andres Virchis
  • Kent
    • Canterbury, Kent, United Kingdom
      • Recruiting
      • Kent and Canterbury Hospital
      • Principal Investigator: Christopher Pocock
    • Maidstone, Kent, United Kingdom
      • Recruiting
      • Maidstone Hospital
      • Principal Investigator: Saad Rassam
    • Orpington, Kent, United Kingdom
      • Recruiting
      • Princess Royal Hospital
      • Principal Investigator: Corrine De Lord
  • London
    • Woolwich, London, United Kingdom
      • Recruiting
      • Queen Elizabeth Hospital
      • Principal Investigator: Corrine De Lord
  • Middlesex
    • Isleworth, Middlesex, United Kingdom
      • Recruiting
      • West Middlesex University Hospital
      • Principal Investigator: Magda Alobaidi
    • Southall, Middlesex, United Kingdom
      • Recruiting
      • Ealing Hospital
      • Principal Investigator: Richard Kaczmarski
    • Uxbridge, Middlesex, United Kingdom
      • Recruiting
      • Hillingdon Hospital
      • Principal Investigator: Richard Kaczmarski
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom
      • Recruiting
      • Belfast City Hospital
      • Principal Investigator: Paul Kettle
  • Somerset
    • Bath, Somerset, United Kingdom
      • Recruiting
      • Royal United Hospital
      • Principal Investigator: Christopher Knechtli
    • Weston-super-Mare, Somerset, United Kingdom
      • Recruiting
      • Weston General Hospital
      • Principal Investigator: Philip Robson
  • Staffordshire
    • Burton-upon-Trent, Staffordshire, United Kingdom
      • Recruiting
      • Queens Hospital
      • Principal Investigator: Humayun Ahmad
  • Tyne and Wear
    • Gateshead, Tyne and Wear, United Kingdom
      • Recruiting
      • Queen Elizabeth Hospital
      • Principal Investigator: Scott Marshall
  • West Midlands
    • Birmingham, West Midlands, United Kingdom
      • Recruiting
      • Queen Elizabeth Hospital
      • Principal Investigator: Paul Moss
  • West Yorkshire
    • Bradford, West Yorkshire, United Kingdom
      • Recruiting
      • Bradford Royal Infirmary
      • Principal Investigator: Adrian Williams
    • Keighley, West Yorkshire, United Kingdom
      • Recruiting
      • Airdale General Hospital
      • Principal Investigator: Chetan Patalappa
    • Leeds, West Yorkshire, United Kingdom
      • Recruiting
      • St James University Hospital
      • Principal Investigator: Peter Hillmen
  • Wiltshire
    • Salisbury, Wiltshire, United Kingdom
      • Recruiting
      • Salisbury District Hospital
      • Principal Investigator: Jonathan Cullis
  • Wirral
    • Upton, Wirral, United Kingdom
      • Recruiting
      • Arrowe Park Hospital
      • Principal Investigator: Ranjit Dasgupta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. CLL/SLL requiring treatment by NCI/IWCLL 2008 criteria. At least one of the following criteria:

   1. Progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia.
   2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
   3. Massive (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
   4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months.
2. No prior cytotoxic or targeted therapy for CLL

3. Full-dose R-FC considered inappropriate for at least one of the following reasons

   1. Age 75 or greater
   2. WHO performance status 2 or 3
   3. Cardiac impairment (NYHA class II)
   4. Respiratory impairment (bronchiectasis or moderate COPD)
   5. Renal impairment (estimated Glomerular Filtration Rate (eGFR) 10-30 ml/min)
   6. Any other significant co-morbidity or factor that makes R-FC inappropriate
4. Considered able to tolerate Chl at the dose used in the LRF CLL4 trial (10mg/m2 d1-7)
5. Written informed consent

Exclusion Criteria:

1. Neutrophil count less than 1.0 x 109/l or platelet count less than 50 x 109/l unless due to CLL
2. Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia
3. Active infection
4. Seropositivity for HIV, HCV or HBV (surface antigen or and core antibody)
5. Severe renal impairment (eGFR less than 10ml/min)
6. Severe hepatic impairment (serum bilirubin more than twice the upper limit of normal) unless due to CLL or Gilbert's syndrome.
7. Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg od
8. Prior treatment with monoclonal antibody therapy within the last 3 months.
9. Yellow fever vaccination within 4 weeks prior to treatment start
10. Known hypersensitivity to ofatumumab, bendamustine or chlorambucil or any of their excipients
11. CNS involvement with CLL
12. History of Richter transformation
13. Concomitant malignancies within the last 3 years except successfully treated non-melanoma skin cancer or carcinoma in situ.
14. Major surgery within 28 days prior to randomisation
15. WHO performance status 4
16. Severe cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia (excluding extra systoles or minor conduction abnormalities) unless controlled by therapy.
17. 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
18. Treatment within a clinical trial within 30 days prior to trial entry.
19. Adult patient under tutelage (not competent to sign informed consent).
20. Pregnant or lactating women.
21. 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.
22. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ofatumumab-Chlorambucil; Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Chlorambucil: 10mg/m2 po days 1-7	Drug: Chlorambucil; Other Names: Leukeran; Drug: Ofatumumab; Other Names: Arzerra
Experimental: Ofatumumab-Bendamustine; Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Bendamustine: 70mg/m2 iv days 1 and 2	Drug: Bendamustine; Other Names: Levact; Drug: Ofatumumab; Other Names: Arzerra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Calculated from the date of randomisation to the date of progression or death, or the censor date.	There are three pre-planned analyses of the PFS primary endpoint: end recruitment (approx 150 events); 300 events (after a minimum 12 months follow up for all patients), 400 events (after a minimum 24 months follow up for all patients)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response	Response duration is defined as the time from when the criteria for partial or complete response are met until the first documentation of relapse or progression.	6 years (after 2 years follow up of the last patient recruited)
Overall survival	Overall survival is defined as the time from initiation of study treatment to death, irrespective of cause or subsequent treatment. Patients still alive at the time of analysis will be censored at the date last seen alive at last follow up.	6 years (after 2 year follow up of the last patient recruited)
Time to treatment failure	Time to treatment failure is defined as the time from initiation of study treatment to death, disease progression, or initiation of alternative treatment due to failure to achieve a complete or partial response to the study treatment.	6 years (after 2 year follow up of the last patient recruited)
Toxicity	Haematological toxicity will be reported in accordance with the 2008 NCI/IWCLL guidelines. Non-haematological toxicity will be reported in accordance with the current Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.	6 years (after 2 years follow up of the last patient recruited)
Treatment dose administered	The number of cycles of treatment and cumulative dose of individual drugs administered will be summarised for each treatment group separately and compared across treatment groups	5 years (assuming last patient in receives 12 cycles of treatment)
Quality of life	Quality of life will be assessed using the EQ-5D; EQ-VAS; EORTC QLQ-C30 and EORTC QLQ-CLL16 questionnaires. To standardise the raw scores, they will be linearly transformed into 0-to-100 scores.	6 years (after 2 years follow up of the last patient recruited)
Health Economic analysis	The economic evaluation will take the form of a cost-effectiveness analysis with the differential cost of the alternative treatments will be related to their differential benefits in terms of quality-adjusted life years (QALYs). Incremental cost-utility ratios will be estimated based on QALY estimates. A range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis. The use of bootstrapping and cost-effectiveness acceptability curves will facilitate a measure of variability around cost-effectiveness estimates. Sensitivity analysis will be used to consider the importance of sources of uncertainty other than sample variation (e.g. unit costs, discount rates). A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment cost-effectiveness.	6 years (after 2 years follow up of the last patient recruited)
Analysis of frailty and co-morbidity	Patients outcomes will be compared across patient subgroups defined by CIRS, performance status, Vulnerable Elders Survey-13, Groningen Frailty Index (GFI) questionnaires and the Timed 'Up and Go' test.	Baseline, 2 months post treatment
Predictive value of biomarkers	Patient outcomes will be compared across patient subgroups defined by clinical (e.g. age, sex, stage) and laboratory (e.g. chromosomal, abnormalities, IGHV mutation status, TP53 mutation status).	Baseline, every 6 months until 42 months from study entry, disease progression
Response	Response following initial therapy will be assessed in accordance with the revised (2008) NCI/IWCLL response criteria applicable to CLL. Minimal residual disease will be assessed by multicolour flow cytometric analysis of bone marrow aspirate samples taken 2 months after completing treatment and of blood samples taken 2 and 6 months after completing treatment.	Baseline; 2 months post treatment; 6 months post treatment

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: GlaxoSmithKline; Chugai Pharma USA; Napp Pharmaceuticals Limited

Publications and helpful links

Helpful Links

• ISRCTN
• CancerHelp UK

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: August 30, 2012
• First Submitted That Met QC Criteria: September 4, 2012
• First Posted (Estimate): September 5, 2012

Study Record Updates

• Last Update Posted (Estimate): October 15, 2012
• Last Update Submitted That Met QC Criteria: October 12, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: Ofatumumab; Bendamustine; Chronic Lymphocytic Leukaemia; Less fit; CD20 antibody; Chlorambucil
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Bendamustine Hydrochloride; Ofatumumab; Chlorambucil
• Other Study ID Numbers: OMB114578; 2011-000919-22 (EudraCT Number); 009988575 (Registry Identifier: ISRCTN)