A Trial Looking at Rituximab and Chemotherapy as a Treatment for Follicular Lymphoma in Elderly Patients (PACIFICO)

Purine-Alkylator Combination In Follicular Lymphoma Immuno-Chemotherapy for Older Patients: a Phase III Comparison of First-line R-CVP Versus R-FC

The purpose of this study is to determine whether R-FC is more beneficial that R-CVP in the treatment of older patients (aged 60 or over) with Follicular Lymphoma (FL).

Study Overview

• Status: Unknown
• Conditions: Follicular Lymphoma
• Intervention / Treatment: Drug: Rituximab; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Prednisolone; Drug: Fludarabine

Detailed Description

FL predominantly affects the elderly, yet the optimum treatment for older patients with the disease has not been defined. The present study aims to address this question by comparing the drug combination that is currently considered the gold-standard (R-CVP) with a newer combination (R-FC) that might be more effective without being significantly more toxic. In order to take into account the balance between efficacy and toxicity, a dual primary endpoint has been employed: progression-free survival and toxicity in the form of grade 3-4 infection.

• Study Type: Interventional
• Enrollment (Anticipated): 680
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kathryn Marley; Phone Number: +44 (0)151 794 8897; Email: kathryn.marley@liverpool.ac.uk
• Study Contact Backup: Name: James Dodd; Phone Number: +44 (0)151 795 5288; Email: jpdodd@liverpool.ac.uk

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom
    • Recruiting
    • Aberdeen Royal Infirmary
    • Principal Investigator: Dominic Culligan, Dr.
  • Bangor, United Kingdom
    • Recruiting
    • Ysbyty Gwynedd
    • Principal Investigator: David Edwards, Dr.
  • Birmingham, United Kingdom
    • Recruiting
    • Birmingham Heartlands
    • Principal Investigator: Don Milligan, Professor
  • Bournemouth, United Kingdom
    • Recruiting
    • Royal Bournemouth Hospital
    • Principal Investigator: Helen McCarthy, Dr
  • Bradford, United Kingdom
    • Recruiting
    • Bradford Royal Infirmary
    • Principal Investigator: Lisa Newton, Dr
  • Bristol, United Kingdom
    • Recruiting
    • Frenchay Hospital
    • Principal Investigator: Sophie Otton, Dr.
  • Burton-upon-Trent, United Kingdom
    • Recruiting
    • Queen's Hospital, Burton
    • Principal Investigator: Humayun Ahmad, Dr.
  • Cambridge, United Kingdom
    • Recruiting
    • Addenbrookes Hospital
    • Principal Investigator: George Follows, Dr
  • Canterbury, United Kingdom
    • Recruiting
    • Kent and Canterbury Hospital
    • Principal Investigator: Christopher Pocock, Dr.
  • Cardiff, United Kingdom
    • Recruiting
    • Velindre Hospital
    • Principal Investigator: Eve Gallop-Evans, Dr.
  • Chester, United Kingdom
    • Recruiting
    • Countess of Chester
    • Principal Investigator: Salaheddin Tueger, Dr.
  • Crewe, United Kingdom
    • Recruiting
    • Leighton Hospital
    • Principal Investigator: Kamaraj Karunanithi, Dr.
  • Davyhulme, United Kingdom
    • Recruiting
    • Trafford General Hospital
    • Principal Investigator: Patrick Carrington, Dr.
  • Dudley, United Kingdom
    • Recruiting
    • Russels Hall Hospital
    • Principal Investigator: Savio Fernandes, Dr.
  • Exeter, United Kingdom
    • Recruiting
    • Royal Devon & Exeter Hospital
    • Principal Investigator: Anthony Todd, Dr.
  • Falkirk, United Kingdom
    • Recruiting
    • Falkirk & District Royal Infirmary
    • Principal Investigator: Marie Hughes, Dr.
  • Gateshead, United Kingdom
    • Recruiting
    • Queen Elizabeth Hospital
    • Principal Investigator: Scott Marshall, Dr.
  • Gillingham, United Kingdom
    • Recruiting
    • Medway Maritime Hospital
    • Principal Investigator: M Aldouri, Dr
  • Glasgow, United Kingdom
    • Recruiting
    • Beatson Oncology Centre
    • Principal Investigator: Pam McKay, Dr.
  • Glasgow, United Kingdom
    • Recruiting
    • Royal Alexandra Hospital
    • Principal Investigator: Alison Sefcick
  • Harrogate, United Kingdom
    • Recruiting
    • Harrogate District Foundation Trust
    • Principal Investigator: Claire Hall, Dr.
  • Harrow, United Kingdom
    • Recruiting
    • Northwick Park Hospital
    • Principal Investigator: Charalampia Kyriakou, Dr.
  • Hayes, United Kingdom
    • Recruiting
    • Princess Royal Hospital, Bromley
    • Principal Investigator: Ankil Lakhani, Dr.
  • Huddersfield, United Kingdom
    • Recruiting
    • Huddersfield Royal Infirmary
    • Principal Investigator: Sylvia Feyler, Dr.
  • Hull, United Kingdom
    • Recruiting
    • Castle Hill Hospital
    • Principal Investigator: Russell Patmore, Dr.
  • Inverness, United Kingdom
    • Recruiting
    • Raigmore Hospital,
    • Principal Investigator: Peter Forsyth, Dr.
  • Ipswich, United Kingdom
    • Recruiting
    • Ipswich Hospital
    • Principal Investigator: Jamie Morgan, Dr.
  • Kettering, United Kingdom
    • Recruiting
    • Kettering General Hospital
    • Principal Investigator: Matthew Lyttelton, Dr.
  • Kings Lynn, United Kingdom
    • Recruiting
    • The Queen Elizabeth Hospital, Kings Lynn
    • Principal Investigator: Lisa Cooke, Dr
  • Leeds, United Kingdom
    • Recruiting
    • St James University Hospital
    • Principal Investigator: Rod Johnson, Dr.
  • Leicester, United Kingdom
    • Recruiting
    • Leicester Royal Infirmary
    • Principal Investigator: Ben Kennedy, Dr.
  • Liverpool, United Kingdom
    • Recruiting
    • Royal Liverpool University Hospital
    • Principal Investigator: Andrew Pettitt, Dr.
  • Liverpool, United Kingdom
    • Recruiting
    • University Hospital Aintree
    • Principal Investigator: Barrie Woodcock, Dr.
  • London, United Kingdom
    • Recruiting
    • Royal Free Hospital
    • Principal Investigator: Christopher McNamara, Dr.
  • London, United Kingdom
    • Recruiting
    • Kings College Hospital
    • Principal Investigator: Robert Marcus, Dr.
  • London, United Kingdom
    • Recruiting
    • St Bartholomews Hospital
    • Principal Investigator: Silvia Montoto, Dr.
  • London, United Kingdom
    • Recruiting
    • University College Hospital
    • Principal Investigator: Kirit Ardeshna, Dr.
  • London, United Kingdom
    • Recruiting
    • Guys & St Thomas Hospital
    • Principal Investigator: Paul Fields, Dr.
  • Londonderry, United Kingdom
    • Recruiting
    • Altnagelvin Hospital
    • Principal Investigator: Feargal McNicholl, Dr.
  • Luton, United Kingdom
    • Recruiting
    • Luton & Dunstable Hospital
    • Principal Investigator: Peter Hoskin, Dr.
  • Maidstone, United Kingdom
    • Recruiting
    • Kent Oncology Centre
    • Principal Investigator: Saad Rassam, Dr,
  • Manchester, United Kingdom
    • Recruiting
    • Manchester Royal Infirmary
    • Principal Investigator: Kate Ryan, Dr
  • Manchester, United Kingdom
    • Recruiting
    • The Christie Hospital
    • Principal Investigator: John Radford, Professor
  • Newcastle upon Tyne, United Kingdom
    • Recruiting
    • Royal Victoria Infirmary
    • Principal Investigator: Anne Lennard, Dr
  • Northampton, United Kingdom
    • Recruiting
    • Northampton General Hospital
    • Principal Investigator: Angela Bowen, Dr.
  • Northwood, United Kingdom
    • Recruiting
    • Mount Vernon Hospital
    • Principal Investigator: Kirit Ardeshna, Dr.
  • Nottingham, United Kingdom
    • Recruiting
    • Nottingham City Hospital
    • Principal Investigator: Andrew McMillan, Dr.
  • Plymouth, United Kingdom
    • Recruiting
    • Derriford Hospital
    • Principal Investigator: Simon Rule, Dr.
  • Prescot, United Kingdom
    • Recruiting
    • Whiston Hospital
    • Principal Investigator: James Nicholson, Dr.
  • Romford, United Kingdom
    • Recruiting
    • Queens Hospital
    • Principal Investigator: Alison Brownell, Dr.
  • Salford, United Kingdom
    • Recruiting
    • Salford Royal Hospital
    • Principal Investigator: Simon Jowitt, Dr.
  • Salisbury, United Kingdom
    • Recruiting
    • Salisbury District Hospital
    • Principal Investigator: Jonathan Cullis, Dr
  • Scunthorpe, United Kingdom
    • Recruiting
    • Diana Princess of Wales Hospital
    • Principal Investigator: Hanna Ciepluch, Dr.
  • Sheffield, United Kingdom
    • Recruiting
    • Royal Hallamshire Hospital
    • Principal Investigator: Josh Wright, Dr
  • Slough, United Kingdom
    • Recruiting
    • Wexham Park Hospital
    • Principal Investigator: Simon Moule, Dr.
  • South Shields, United Kingdom
    • Recruiting
    • South Tyneside District General Hospital
    • Principal Investigator: Simon Lyons, Dr.
  • Southampton, United Kingdom
    • Recruiting
    • Southampton General Hospital
    • Principal Investigator: Peter Johnson, Professor
  • Southampton, United Kingdom
    • Recruiting
    • Basingstoke and North Hampshire Hospital
    • Principal Investigator: Alison Milne, Dr
  • Southampton, United Kingdom
    • Recruiting
    • St Richards Hospital
    • Principal Investigator: Philip Bevan, Dr.
  • St Asaph, United Kingdom
    • Recruiting
    • Glan Clwyd Hospital
    • Principal Investigator: Christine Hoyle, Dr.
  • Stafford, United Kingdom
    • Recruiting
    • Stafford District General Hospital
    • Principal Investigator: Paul Revell, Dr.
  • Stevenage, United Kingdom
    • Recruiting
    • Lister Hospital
    • Principal Investigator: Judith Hanslip, Dr.
  • Sunderland, United Kingdom
    • Recruiting
    • Sunderland Royal Hospital
    • Principal Investigator: Simon Lyons, Dr.
  • Swindon, United Kingdom
    • Recruiting
    • Great Western Hospital
    • Principal Investigator: Norbert Blesing, Dr.
  • Torquay, United Kingdom
    • Recruiting
    • Torbay District General Hospital
    • Principal Investigator: Deborah Turner, Dr.
  • Truro, United Kingdom
    • Recruiting
    • Royal Cornwall Hospital
    • Principal Investigator: Anton Kruger, Dr.
  • Uxbridge, United Kingdom
    • Recruiting
    • Hillingdon Hospital
    • Principal Investigator: Richard Kaczmarski, Dr.
  • Wakefield, United Kingdom
    • Recruiting
    • Pinderfields General Hospital
    • Principal Investigator: Paul Moreton, Dr.
  • Watford, United Kingdom
    • Recruiting
    • West Herts
    • Principal Investigator: Justin Harrison, Dr
  • Wirral, United Kingdom
    • Recruiting
    • Arrowe Park Hospital
    • Principal Investigator: Ranjit Dasgupta, Dr
  • Worcester, United Kingdom
    • Recruiting
    • Worcestershire Acute Hospitals NHS Trust
    • Principal Investigator: Salim Shafeek, Dr
  • Worthing, United Kingdom
    • Recruiting
    • Worthing Hospital
    • Principal Investigator: Santhosh Narat, Dr.
  • York, United Kingdom
    • Recruiting
    • York District Hospital
    • Principal Investigator: Laura Munro, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed follicular lymphoma (grade 1,2, and 3a with material available for central review)
• Ann Arbor stage II-IV
• Aged 60 years or over, or aged less than 60 but anthracycline-based therapy contra-indicated
• No prior systemic therapy (one episode of prior local radiotherapy is allowed)
• At least one of the following criteria for initiation of treatment:
• Rapid generalized disease progression in the preceding 3 months
• Life threatening organ involvement
• Renal or macroscopic liver infiltration
• Bone lesions
• Presence of systemic symptoms or pruritus
• Haemoglobin < 10 g/dL or WBC < 3.0 × 109/L or platelet counts < 100 × 109/L due to marrow involvement
• Adequate haematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow):
• Haemoglobin ≥ 8.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Written Informed Consent

Exclusion Criteria:

• Overt transformation to diffuse large B-cell lymphoma
• Grade 3b follicular lymphoma
• Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis)
• WHO performance status 3 or 4
• Impaired renal function defined as estimated Glomerular filtration rate (eGFR) < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) formula
• Impaired hepatic function defined as serum bilirubin more than twice upper limit of normal (unless due to lymphoma or Gilbert's syndrome)
• Life expectancy less than 12 months
• Pre-existing neuropathy
• Active auto-immune haemolytic anaemia
• Serological evidence of infection with HIV, hepatitis B (positivity for surface antigen or core antibody) or hepatitis C
• Allergy to murine proteins
• Corticosteroid treatment during the last 4 weeks, unless administered at a dose equivalent to no more than prednisolone 20mg/day continuously or a single course of prednisolone 1 mg/kg for up to 7 days
• Concomitant malignancies except adequately treated localised non-melanoma skin cancer or adequately treated in situ cervical cancer, or cancers that have been in remission for at least 5 years following surgery with curative intent.
• Major surgery (excluding lymph node biopsy) within 28 days prior to randomisation
• Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
• Treatment within a clinical trial within 30 days prior to trial entry
• Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent
• Adult patient under tutelage (not competent to sign informed consent)
• Pregnant or lactating women
• All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom

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: R-CVP; Repeated every 21 days for up to 8 cycles with response assessment after 4 cycles. Responders (PR/CR) after 8 cycles will receive Rituximab maintenance therapy for 2 years (12 bi-monthly cycles).	Drug: Rituximab; Rituximab 375mg/m2 IV day 1,repeated every 21 days for 8 cycles. All patients who have achieved a CR or PR to induction therapy will receive rituximab maintenance (375mg/m2 every 2 months for 2 years).; Other Names: Mabthera; Drug: Cyclophosphamide; Cyclophosphamide 250mg/m2 PO day 1-3, repeated every 21 days for 4 (R-FC) or 8 cycles (R-CVP); Other Names: Cyclophosphamide monohydrate; Drug: Vincristine; Vincristine 1.4mg/m2 IV day 1,repeated every 21 days for 8 cycles.; Other Names: vincristine sulfate; Drug: Prednisolone; Prednisolone 40mg/m2 PO day 1-5, repeated every 21 days for 8 cycles.; Other Names: Deltacortril
Experimental: R-FC; Repeated every 21 days for 4 cycles. Responders (PR/CR) after 4 cycles will receive 4 further cycles of Rituximab only. Responders after 8 cycles will receive Rituximab maintenance therapy for 2 years (12 bi-monthly cycles).	Drug: Cyclophosphamide; Cyclophosphamide 250mg/m2 PO day 1-3, repeated every 21 days for 4 (R-FC) or 8 cycles (R-CVP); Other Names: Cyclophosphamide monohydrate; Drug: Fludarabine; Fludarabine 40mg/m2 PO day 1-3,repeated every 21 days for 4 cycles; Other Names: Fludara

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		30 months
Toxicity	The second primary outcome measure is grade 3-4 infection occurring anytime from the start of treatment until 6 months following the last dose of treatment, and this will be used as the toxicity end-point. Toxicity will be measured according to standard National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 following each cycle of treatment and at each subsequent follow-up visit until 6 months following the last dose of treatment.	36 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	End of study
Response rates (overall, complete and partial) following initial therapy	24 weeks
Response rates following maintenance therapy	30 months
Response duration	30 months
Time to next treatment	End of study
Rate of large cell transformation	End of study
Response to second-line therapy	30 months
Number of treatment cycles delivered	30 months
Cumulative dose of individual drugs administered	30 months
Quality of life	End of study
Cost effectiveness	End of study

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: Roche Pharma AG; Cancer Research UK; Liverpool University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Andrew Pettitt, Professor, University of Liverpool and Royal Liverpool and Broadgreen University Hospitals Trust

Publications and helpful links

Helpful Links

• Cancer Research UK

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Anticipated): September 1, 2016
• Study Completion (Anticipated): September 1, 2016

Study Registration Dates

• First Submitted: February 24, 2011
• First Submitted That Met QC Criteria: February 24, 2011
• First Posted (Estimate): February 25, 2011

Study Record Updates

• Last Update Posted (Estimate): May 6, 2011
• Last Update Submitted That Met QC Criteria: May 4, 2011
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Keywords: Rituximab; Follicular Lymphoma; Non-Hodgkin's Lymphoma; Older; PACIFICO; R-CVP; R-FC
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Prednisolone; Cyclophosphamide; Rituximab; Fludarabine; Vincristine
• Other Study ID Numbers: ISRCTN99217456; 2008-004759-31 (EudraCT Number)