An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with advanced stage, asymptomatic, non-bulky follicular lymphoma

 
An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with advanced stage, asymptomatic, non-bulky follicular lymphoma
(Grades 1, 2 and 3a)
 
 
 
 
 
 
September 2007
 
 
 
 
 
 
 
 
 
 
 
Chief Investigator:
 
 
Dr Kirit Ardeshna
Mount Vernon Cancer Centre, London
 
 
 
 
_____________________________________
 
 
 
Version 7.1 (Final) 13/09/07
 
General Information
 
This document describes the Watch and Wait trial and provides information about procedures for entering patients into it. The protocol should not be used as an aide-memoire or guide for the treatment of other patients. Every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to the registered investigators in the trial, but centres entering patients for the first time are advised to contact the Lymphoma Trials Office, London to confirm they have the most up to date version. Clinical problems relating to this trial should be referred to the Chief Investigator.
 
·                Compliance
The study will be conducted in compliance with the protocol, GCP, EU Directive 2001, Data Protection Act (UCL data protection reference Z6364106/2006/3/36), NHS Research Governance and other regulatory requirements as appropriate.
·                Sponsor
University College London
·                Authorisation
Dr. Kirit Ardeshna
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact details:
 
Chief Investigator and Medical Expert:
Dr Kirit Ardeshna
Mount Vernon Cancer Centre
Rickmansworth Road
Northwood
Middlesex, HA6 2RN
Tel  +44 (0) 1923 844413 
(Mobile number via Lymphoma Trials Office:
 +44 (0) 20 7679 9860 )
Fax +44 (0) 1923 844138
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Clinical Trial Coordinator:
 
Professor David C. Linch
Department of Haematology
University College Hospital
98 Chenies Mews
London WC1E 6HX
 
Tel  +44 (0) 20 7679 6221 
Fax + 44 (0) 20 7679 6222
 
Watch and Wait Trial Co-ordinator:
Lindsey Stevens
Lymphoma Trials Office
Cancer Research UK and UCL Cancer Trials Centre
90 Tottenham Court Road
London W1T 4TJ
Tel  +44 (0) 20 7679 9868 
Fax +44 (0) 20 7679 9861
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Data Manager:
Nadjet El-Mehidi
Lymphoma Trials Office
Cancer Research UK and UCL Cancer Trials Centre
90 Tottenham Court Road
London W1T 4TJ
Tel  +44 (0) 20 7679 9105 
Fax +44 (0) 20 7679 9861
 
 
 
Statistician
Dr Wendi Qian
MRC Clinical Trials Unit
 
222 Euston Road
London NW1 2DA
Tel  + 44 (0) 20 7670 4705 
Fax +44 (0) 20 7670 4818
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Histopathologist:
Dr. Andrew Jack
Haematological Malignant Diagnosis Service
Algernon Firth Building
University of Leeds
Leeds LS2 9JT
 
 
 
 
Lymphoma Trials Office (for patient registration and randomisation)
Cancer Research UK and UCL Cancer Trials Centre
90 Tottenham Court Road, London W1T 4TJ, United Kingdom
 
Tel:  +44 (0) 207 679 9860  (9am to 5pm Monday to Friday) Fax: +44 (0) 207 679 9861
 
 
 
 
 
 
 
 
 
 
 
 
Contents:
 
Page Number
General Information
2
Contact details
3
Trial outline
5
Introduction
6
Trial design and objective
7
Primary end-point
7
Secondary end-points
7
Quality of Life end-points
7
Eligibility criteria
8
Exclusion criteria
8
Treatment
9
Baseline assessment
9
Patient registration and randomisation
10
Follow up assessment
11
Initiation of treatment
13
Evaluation criteria
13
Toxicity
15
Serious Adverse Events
17
Reasons for stopping the protocol
18
Statistical considerations
19
a)
Sample size
 
b)
Accrual
 
c)
Planned analyses
 
d)
Data monitoring and ethics committee
 
e)
Independent trial steering committee
 
f)
Trial management
 
Quality assurance
19
Ethics and governance
21
Publication
21
Quality of Life issues
22
Handling of blood and bone marrow
24
 
References
25
Appendix 1 (Summary of Investigations)
Appendix 2 (Quality of Life Questionnaire)
Appendix 3 (Serology for Hepatitis B)
 

 
1. Trial outline
 
Newly diagnosed, previously untreated patients with advanced stage, asymptomatic, non-bulky follicular lymphoma who consent to trial entry may be registered and, if eligible for randomisation, will be randomised to one of two arms (Arm A and Arm C). Patients in arm A (Watch and Wait, W&W) should be carefully observed and any spontaneous clinical remissions carefully documented. In arm C (rituximab treatment and maintenance R4+RM), patients will receive four infusions of rituximab (375mg/M²) over a four week period followed by maintenance treatment with rituximab. Maintenance treatment consists of a single rituximab dose of 375mg/M2 given at 2 monthly intervals after the first four infusions of treatment rituximab. Maintenance treatment will therefore start at week 12 and finish at week 100. A single dose of rituximab will be given at 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92 and 100 weeks (i.e. for approximately 24 months), providing there is no progression that requires chemotherapy or radiotherapy. Once entered into the trial patients should be seen one month after randomisation (W&W arm) or at the time of the 4th cycle of rituximab treatment (R4+RM arm) to ensure there is no significant disease progression. Subsequent evaluations should take place at least every 2 months for the first 2 years. Following this the follow up intervals can be increased to 3 monthly. The trial design is shown below. (A summary of investigations is given in Appendix 1). Quality of life will be assessed in both arms pre-randomisation and for a total of 4 years post randomisation.
  
 

*Participating countries only
 
 
 

 
2. Introduction
 
The policy of watchful-waiting in asymptomatic, low-grade lymphomas was advocated by the Stanford group over twenty years ago.1 Their experience was updated in 1984 in a seminal paper published in the New England Journal of Medicine.2 This analysis revealed that nearly one quarter of untreated patients underwent some form of spontaneous regression and that the median time until chemotherapy was required was three years. This experience was confirmed in a number of other centres and several randomised trials of watch-and-wait versus immediate chemotherapy were performed.3-5 In a study from the NCI USA, 89 asymptomatic patients were randomised to either watch-and-wait or an aggressive combined modality regimen (ProMACE-MOPP).3 No difference in survival was seen, although this small study had very limited power and only short follow-up was reported. The GELF group carried out a randomised trial in asymptomatic patients with low tumour bulk.4 Sixty-six patients were in the ‘no initial treatment’ group, sixty-four in a chemotherapy group (prednimustine) and sixty-three in an interferon treatment group. In the patients initially given no therapy, the median time to initiation of treatment was twenty-four months. There was no difference in the overall survival at five years in the three arms of the trial, although the number of patients in each group was small and the length of follow-up relatively short for this disease.
 
The largest randomised trial of watchful waiting versus initial chemotherapy (Chlorambucil) was started by the British National Lymphoma Investigation in 1981.6 Three hundred and nine patients were randomised in this trial and there was a median follow-up of sixteen years at the time of the analysis. This trial confirms that there is no long-term survival advantage to the early initiation of chemotherapy and the median time to initiation of chemotherapy in the watch and wait arm was 31 months. Interestingly, the actuarial chance of not requiring chemotherapy at ten years was 19%.
 
This trial thus supports the widely practiced strategy of ‘watch and wait’ in asymptomatic patients. It is however, a negative approach in so far as the aim is to maximise quality of life rather than to effect a cure or significantly improve survival. There is thus still a need to carry out well-designed trials of potentially curative therapy in younger patients even though they are asymptomatic. Total body irradiation and stem cell transplantation in first remission may prolong the period of remission in some patients, but there is little evidence that it is curative7 and there is currently little enthusiasm for this approach (EORTC trial closed due to very poor recruitment). Allogeneic transplantation may be curative in some patients8 but even with reduced intensity conditioning9 the procedure-related mortality is considerable and few patients would opt for this strategy as part of initial therapy. The use of rituximab plus CHOP has provided exciting pilot data with the median disease-free survival not reached at six years.10 This approach clearly merits further exploration in a large Phase III trial. 
 
For the time being, however, a watch-and-wait approach remains the ‘standard’ for most asymptomatic patients, most physicians preferring to defer chemotherapy until disease progression, based on the assumption that this results in an improved quality of life in these asymptomatic patients by not exposing the patients to the toxic side effects of chemotherapy, reducing hospital visits and by decreasing the need for blood tests. This assumption has never been formally assessed and indeed there is anecdotal evidence that, at least for some patients, this strategy may lead to a worse quality of life, as patients can find being diagnosed with a malignant condition and not receive treatment psychologically distressing.
The aim of this trial is to explore the value of rituximab alone in newly diagnosed asymptomatic patients in an attempt to significantly delay the time to initiation of chemotherapy and to explore the associated quality of life changes which this strategy may bring compared with a watchful waiting approach. Rituximab used alone induces a response in approximately 50% of relapsed and resistant patients with CD20 positive low-grade lymphoma.11 When used alone at an earlier stage of disease, the response rate is higher and in a study from France the response rate was 73%, with 57% of patients achieving a complete molecular remission in the blood.12
 
A randomised trial is now required to determine the magnitude of any delay in initiating chemotherapy that can be induced by use of rituximab therapy, and its clinical utility.
3. Trial design and objective
 
A randomised phase III trial to determine whether initial treatment with rituximab in patients with advanced stage asymptomatic follicular lymphoma (grades 1, 2 and 3a) results in a significant delay in the initiation of chemotherapy or radiotherapy and the impact of each strategy on patient-related quality of life.
4. Primary end-point
1. Time to initiation of therapy (chemotherapy or radiotherapy)
5. Secondary end-points 
1.   The frequency of clinical spontaneous remissions
2.   Response at 25 months
3.   Cause specific survival
4.   Overall survival
6 Quality of Life end-points
 
Primary Quality of Life Objectives
 
1.   To determine whether immediate treatment with rituximab results in increased functional well-being 6 months after randomisation.
2.   To determine whether deferring treatment results in increased anxiety and depression 6 months after randomisation.
3.   To determine whether increased hospital day case attendances for the administration of rituximab and the treatment related side effects experienced during and after the administration of rituximab impact negatively on well being 6 months after randomisation.
 
Secondary Quality of Life objectives
 
All of the above questions at 12, 24 and 36 months.
Exploratory analyses
All the functions and domains will be explored at all time points, and by summarising the longitudinal data, by methods such as ‘area under the curve’, but these analyses will be considered as hypothesis generating rather than definitive analyses.
 
7. Eligibility criteria
 
·         Minimum age 18 years, no upper age limit
·         Follicular lymphoma grade 1, 2 and 3a
·         Stage II, III and IV disease
·         Asymptomatic without “B” symptoms or severe pruritus
·         Blood count: Hb > 10g/dl, Neuts > 1.5 x 109/l, Plts > 100 x 109/l and < 5x109/L circulating tumour cells
·         Renal function: Creatinine < 2 x ULN for reasons other than lymphoma
·         Normal liver function (bilirubin (must not exceed 30 mmol/l) , alanine transaminase/aspartate transaminase, alkaline phosphatase)
o    LDH within normal range
o    Largest nodal or extra nodal mass less than 7cm
o    No more than 3 nodal sites with a diameter more than 3cm
o    No significant serous effusions detectable clinically or on CT (small, clinically non-evident effusions on CT scan are not deemed significant)
o    Spleen enlargement less than or equal to 16cm by CT
·         No other (non-lymphoma) immediately life-threatening disease
·         Must have disease measurable in at least 2 dimensions either clinically or radiologically
·         Entry within 3 months of biopsy with no prior therapy
·         ECOG Performance status 0-1
·         No evidence of histological transformation
·         No second malignancy unless treated with curative intent and patient has been disease free for >2 years
·         If second malignancy was basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma of
the cervix, the patient need only be currently disease free
·         Patient must be able to give informed consent
·         No critical organ failure or organ compression (e.g. ureteric obstruction)
8. Exclusion criteria
 
·         Patients known to be HIV positive
·         Patients with Hepatitis B infection. Please see Appendix 3 for required tests.
·         Pregnant or breast feeding patients
·         Women of childbearing potential not willing to take adequate contraceptive precautions if randomised to rituximab containing arm
 
9. Treatment
 
Arm A (Watch and Wait, W&W)
Patients in arm A (Watch and Wait, W&W) should be carefully observed and any spontaneous clinical remissions carefully documented.
 
Arm C (Rituximab treatment and maintenance, R4+RM)
In arm C (rituximab treatment and maintenance), patients will receive four infusions of rituximab (375mg/M²) over a four week period followed by 2 years maintenance treatment with rituximab.
 
Following the first 4 infusions of treatment rituximab, a single rituximab dose of 375mg/M2 will be given at 2 monthly intervals. Maintenance treatment will therefore start at week 12 and finish at week 100. A single dose of rituximab will be given at 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92 and 100 weeks (i.e. for approximately 24 months), providing there is no progression that requires chemotherapy or radiotherapy.
Rituximab should only be administered in an environment where full resuscitation facilities are available. Pre-medication with paracetamol and a suitable anti-histamine (e.g. diphenhydramine) should always be administered before each infusion of rituximab. The first infusion should start at 50mg/hr; subsequently the rate can be increased by 50mg/hr every 30 minutes up to a maximum of 400mg/hour. Subsequent infusions can be started at a rate of 100mg/hour and increased by 100mg/hour increments every 30 minutes up to a maximum of 400mg/hour. The infusion should be interrupted for severe reactions. The use of bronchodilators, intravenous fluids and corticosteroids may be necessary. Further treatment of patients following resolution of symptoms has rarely resulted in another severe reaction but this is a possibility.
 
Rituximab supply
 
Rituximab will be supplied free of charge by Roche and must be ordered on the forms provided once a patient is randomised to Arm C. Roche will deliver the rituximab directly to the site.
 
Dose reductions
No dose reductions are recommended.
 
Supportive care
Pre-medication with paracetamol and a suitable anti-histamine (e.g. diphenhydramine) should always be administered before each infusion of rituximab. No other routine supportive care is required.
 
10. Baseline assessment
 
1.   Full history and physical examination with site and dimensions of palpable lesions recorded (A maximum of 6 target lesions should be identified. See Response Criteria, page 13).
2.   Measurement and documentation of spleen and liver size and ENT examination if indicated.
3. CT scan chest, abdomen and pelvis with measurement of nodal and extra nodal masses. Neck CT should be performed if cervical lymph nodes palpable. Ideally scans should be performed within 8 weeks of registration. If there has been any clinical progression of the disease in the intervening period then an up to date scan should be performed. MRI, PET, bone scan, ultrasound scan if indicated (not mandatory).
4. Bone marrow and tumour biopsy for histological classification according to WHO classification
5. Full blood count with differential. Blood and bone marrow for DNA and RNA extraction for bcl-2 or t(14;18) PCR analysis and Fc receptor polymorphism. Please see section 23 for details regarding the collection and transportation of samples. In addition specific consent will be sought to allow DNA to be stored for future research studies aimed at identifying factors involved in the pathogenesis of lymphoma and factors which determine response to treatment. (All proposals for the use of this genetic material will need to be approved by an ethical committee before they are carried out. See ethical considerations section 20.).
6. Biochemistry including blood urea, serum creatinine, total protein, albumin, alkaline phosphatase, ALT or AST, LDH, total bilirubin. Serum immunoglobulin quantification and protein electrophoresis, Beta-2 microglobulin.
7. Hepatitis B serology
8. Baseline pre-randomisation questionnaire and post-randomisation (but prior to treatment) questionnaire.
 
**Patients can be consented and registered into the trial and allocated an identifying trial number prior to a bone marrow examination being performed provided they fulfil all other criteria for trial entry. This will allow samples for pcr to be sent at the time of the initial staging marrow and thus prevent the need for a repeat bone marrow examination. Randomisation can only be performed once the result of the staging bone marrow is known in order to allow stratification according to stage.**
11. Patient registration and randomisation
 
Following confirmation of eligibility, written informed consent and verification that baseline pre- randomisation Quality of Life questionnaire has been completed, patient details should be faxed to the Lymphoma Trials Office. Registration will be allowed prior to a bone marrow examination being performed provided the patient fulfils all other criteria for trial entry. This will allow samples for pcr to be sent at the time of the initial staging marrow and thus prevent the need for a repeat bone marrow examination. Randomisation can only be performed once the result of the staging bone marrow is known.
Patients will be centrally randomised. Once a patient has been allocated to a treatment arm the patient should be informed of this and a second baseline quality of life questionnaire should be completed. This second questionnaire is identical to the first questionnaire and must be completed before any treatment is started (R4+RM arm). Patients in the Watch and Wait arm will also have to complete a second questionnaire. Ideally this second questionnaire should be approximately one week after treatment allocation was made. A minimisation technique will be used for random treatment allocation stratifying by institution and according to grade, stage and age. Contact the Lymphoma Trials Office on:      
 

Phone:  +44 (0) 207 679 9860 
Fax: +44 (0) 207 679 9861
between 9am and 5pm, Monday to Friday
                       

 
 
 
 
12. Assessments at follow-up and treatment for all randomised patients
 
All patients should be followed up according to the schedule below, unless new therapy is initiated or patients explicitly withdraw consent from the trial. All patients, regardless of whether or not new therapy is initiated, must complete a Quality of Life questionnaire 4 years from the date of randomisation into the trial. The only patients who will be exempt from completing this questionnaire at 4 months are those who have explicitly withdrawn consent.
 
Assessment Intervals
Patients should be seen one month after randomisation (W&W arm) or when they are receiving their 4th infusion of rituximab (R4+RM arm) to ensure there is no significant disease progression. Subsequent evaluations should take place at least every 2 months for the first 2 years., or until initiation of therapy. Following this the follow up intervals can be increased to 3 monthly, if new therapy has not been initiated.
 
Assessment
At each assessment patients should be evaluated for symptoms suggestive of disease progression including B symptoms. A clinical examination should document any lymphadenopathy and the extent of any hepatosplenomegaly. Blood tests should include full blood count and differential, urea, creatinine and liver function tests.
 
At each assessment in the first 2 years a quality of life questionnaire should be completed by the patient. After this time a questionnaire should be completed every 6 months for 2 years, i.e. 31, 37, 43, and 49 months post randomisation.
 
a) At each clinic visit:
 
·         Quality of Life questionnaire:
To be completed at each clinic visit in the first 2 years and then at 31, 37, 43 and 49 months (see below)
 
·         History:
Enquire about symptoms related to lymphoma including B symptoms
 
·         Examination:
Examine and document lymphadenopathy, hepatomegaly and splenomegaly
 
·         Investigations:
Blood tests:
o   Full blood count with differential
o   Chemistry panel including (Blood urea, serum creatinine, total protein, albumin, alkaline phosphatase, ALT or AST, total bilirubin)
 
b) At selected clinic visits:
 
·         Quality of Life questionnaire
To be completed at each clinic visit in the first 2 years (see above) and then at 31, 37, 43 and 49 months (see above).
 
·         Investigations:
 
·         Blood tests:
o    PCR for bcl-2/t(14;18) in blood if in CR clinically and radiologically at 7, 13 and 25 months. PCR will not be evaluated in real time. Please see section 23 for details regarding the collection and transportation of samples.
Serum immunoglobulins will be measured at 13, 25 and 37 months (in view of prolonged maintenance with rituximab). If abnormalities are found these should be investigated as considered appropriate.
 
·         Bone marrow aspirate and trephine:
 
o    A bone marrow trephine is required for staging locally if patients are in CR clinically and radiologically at 7, 13 and 25 months.
 
o    A bone marrow aspirate for PCR for bcl-2/t (14;18) is also required if patients are in CR clinically and radiologically at 7, 13 and 25 months. Please see section 23 for details regarding the collection and transportation of samples.
 
o    Prior to starting first chemotherapy or radiotherapy a repeat BM should be performed, and also at the end of this first course of chemotherapy or radiotherapy, to properly establish response rates.
 
·         Imaging:
In BOTH arms:
o    Compulsory CT scan at 7 months and 25 months from randomisation
o    CT scan at 13 months if in clinical CR (Arm C) or spontaneous remission (Arm A)
o    CT scan if significant progression suspected
o    CT scan mandatory if chemotherapy or radiotherapy is to be commenced and after a course of chemotherapy or radiotherapy to assess response
 
c) Following initiation of new therapy:
  • Patients will be followed-up 6 monthly
  • Quality of Life questionnaire to be completed prior to the initiation of new treatment and at 4 years from the date of randomisation into the Watch and Wait trial.
 
13. Definition of progression that warrants initiation of treatment chemotherapy/radiotherapy.
 
It is recognised that it is difficult to clearly define when disease progression is sufficient to warrant the initiation of chemotherapy or radiotherapy. The following is suggested guidance:
 
1.   Development of symptomatic enlarged lymph nodes or spleen.
2.   The development of B symptoms or severe pruritus.
3.   Lymphomatous mass >7cm provided it has increased in size by at least 25%.
4.   More than 3 sites with diameter >5cm.
5.   The development of significant serous effusions, clinically or on CT (small, clinically non-evident effusions on CT scan are not an indication to start chemotherapy).
6.   Hb <10g/dl, neuts <1.5x109/l, platelet <100x 109/l not attributable to other causes. If asymptomatic this should persist for >1 month.
7.   Critical or near critical organ involvement or organ compression, e.g. ureteric obstruction, epidural compression.
8.   Patient refusal to remain on watch and waiting policy.
 
A rising LDH is not in itself an indication to initiate therapy but may trigger further investigations.
 
Choice of chemotherapy
This is determined by local practice and is at the choice of the treating physician. Alkylating agents or purine analogues used singly or in combination with other chemotherapeutic agents are expected choices. It is recommended that patients in the watch and wait arm should not receive rituximab alone as their initial therapy. If this happens, this will be considered in the analyses as chemotherapy.
 
Radiotherapy
Administration of radiotherapy will be counted as a primary endpoint.
14. Evaluation criteria
 
Time until initiation of therapy (chemotherapy or radiotherapy)
The primary endpoint is the time until initiation of therapy (chemotherapy or radiotherapy). This endpoint is defined as the time from randomisation until the first day systemic chemotherapy or radiotherapy is given. If rituximab is given to patients in the watch and wait arm this will be considered as initiation of chemotherapy.
 
Cause specific survival
Cause specific survival is defined as time from randomisation to death from lymphoma or immediate therapy related toxicity. Patients who are still alive are censored at the time they were last known to be alive.
 
Overall survival
Overall survival is defined as time from randomisation to death from any cause. Patients who are still alive are censored at the time they were last known to be alive.
 
Response criteria
Response rates are secondary end-points in this trial. The criteria for response evaluation according to Cheson et al13 will be used.
 
During the initial measurement, a maximum of 6 target lesions should be identified. These lesions (lymph nodes and nodal masses)should be selected according to the following features:
 
·        they should be clearly measurable in at least two perpendicular dimensions
·        they should be from as disparate regions of the body as possible
·        they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved
 
Complete remission (CR)
1.   Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalisation of those biochemical abnormalities definitely attributable to NHL for a minimum period of 2 months.
2.   All lymph nodes and nodal massesmust have regressed to normal size (≤1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to 1 cm in their greatest transverse diameter after treatment, or by more than 75% in the sum of the products of the greatest diameters (SPD).
3.   The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. However, no normal size can be specified because of the difficulties in accurately evaluating splenic and hepatic size. Any macroscopic nodules in any organ detectable on imaging techniques should no longer be present. Similarly, other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size.
4.   If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow biopsy of the same site. The sample on which this determination is made must be adequate (should ideally be 20 mm biopsy core).
 
Complete Remission uncertain (CRu [i.e. PR 75%])
Criteria 1 & 3 same as listed above for CR but with one or more of the following features:
 
 i.    A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the SPD. Individual nodes that were previously confluent must have regressed by more than 75% in their SPD compared with the size of the original mass.
ii.    Indeterminate bone marrow (increased number or size of aggregates without cytological or architectural atypia).
 
Partial remission
1.   At least 50% decrease in SPD of the six largest dominant lesions.
2.   No increase in the size of the other nodes, liver, or spleen.
3.   Splenic and hepatic nodules must regress by at least 50% in the SPD.
4.   With the exception of splenic and hepatic nodules, involvement of other organs is considered assessable and not measurable disease.
5.   Bone marrow is irrelevant for determination of a PR because it is assessable and not measurable disease. However, if positive, the cell type should be specified in the report, e.g. large cell lymphoma or low grade lymphoma.
6.   No new sites of disease.
 
No change or stable disease
No change or stable disease is defined as less than a PR (see above) but is not progressive disease (see below).
 
Relapsed disease
Relapsed disease (in patients who achieved CR, CRu (PR 75%)) requires the following:
 
1.   Appearance of any new lesion or increase by 50% in the size of previously involved sites.
2.   50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node.
 
Progressive disease
Progressive disease (PD) (in patients who achieved PR or non responders) requires the following:
 
1.   50% increase from nadir in the SPD of any previously identified abnormal node for PRs or non-responders.
2.   Appearance of any new lesion during or at the end of therapy.
15. Toxicity
 
Expected rituximab toxicity
 
Infusional toxicity - more than 50% of patients experience an infusional-related reaction consisting of fever, chills and rigors which predominantly occurs during the first one or two infusions. Other symptoms include dyspnoea, flushing, angiooedema, nausea, urticaria, rash, fatigue, headache, throat irritation, rhinitis, vomiting and tumour pain. Most of these infusion-related reactions are mild to moderate (grade I, II), 10% of these patients may also experience grade III/IV events with hypotension and bronchospasm. 14
The symptoms are usually reversible with interruption of MabThera infusion and administration of pain relievers, antihistaminics and other supportive care. Infusion related deaths occur at the rate of 4-7 per 10,000 patients treated. The incidence of infusion-related reactions decreases with subsequent infusions.
Rituximab should only be administered in an environment where full resuscitation facilities are available. Pre-medication with paracetamol and a suitable anti-histamine (e.g. diphenhydramine) should always be administered before each infusion of rituximab. The first infusion should start at 50mg/hr; subsequently the rate can be increased by 50mg/hr every 30 minutes up to a maximum of 400mg/hour. Subsequent infusions can be started at a rate of 100mg/hour and increased by 100mg/hour increments every 30 minutes up to a maximum of 400mg/hour. The infusion should be interrupted for severe reactions. The use of bronchodilators, intravenous fluids and corticosteroids may be necessary. Further treatment of patients following resolution of symptoms has rarely resulted in another severe reaction but this is a possibility.
 
Immunological findings - a rapid depletion of B cells is accompanied by a reduction in total serum immunoglobulins in 14% of patients. These reductions were not clinically significant and the incidence of infections was not increased. 0.8% of patients developed weak transient human anti-chimeric antibody responses but these were not associated with clinical or laboratory abnormalities.
 
Cardiac monitoring during and immediately after the infusion is suggested for patients who have pre-existing cardiac conditions. In view of possible hypotension, withholding anti-hypertensive agents prior to and during the infusions can be considered.
 
Tumour lysis syndrome can occur. Patients with high circulating malignant lymphocytes are at greatest risk but these patients are excluded from this study.
 
No studies have been performed in pregnant or breastfeeding women and as immunoglobulin can traverse the placenta pregnant women should not receive the drug and are not eligible for entry into the trial. Effective contraception is mandatory for women of childbearing age during treatment with rituximab and for 12 months afterwards.
 
Dose reductions
No dose reductions are recommended.
 
Supportive care
Pre-medication with paracetamol and a suitable anti-histamine (e.g. diphenhydramine) should always be administered before each infusion of rituximab.
No other routine supportive care is required.
 
16. Serious Adverse Events
 
A Serious Adverse Event (SAE) is defined as any undesirable experience occurring to a patient, whether or not considered related to the protocol treatment. A Serious Adverse Event (SAE) which is considered related to the protocol treatment is defined as a Serious Adverse Drug Reaction (SADR).
 
Adverse events and adverse drug reactions which are considered as serious are those which result in:
 
·         Death or a life threatening event (i.e. the patient was at immediate risk of death at the time the reaction was observed)
·         Hospitalisation or prolongation of hospitalisation
·         Persistent or significant disability/incapacity
·         A congenital anomaly/birth defect
·         Any other medically important condition (i.e. important adverse reactions that are not immediately life threatening or do not result in death or hospitalization but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed above)
 
NB: In this study death due to progression of disease or coexisting medical condition will not be considered as an SAE and must therefore not be reported as an SAE.
 
Reporting procedure
 
Serious adverse events or serious adverse drug reactions
All Serious Adverse Events (SAE), related or not to the protocol treatment, occurring during the treatment period and within 30 days after the last protocol treatment administration, must be reported to the Lymphoma Trials Office. Any late Serious Adverse Drug Reaction (SADR), occurring after this 30-day period also must be reported to the Lymphoma Trials Office. This must be done by fax within 24 hours of the initial observation of the event. The principal investigator will decide if these events are related to the protocol treatment (i.e. unrelated, likely related, and not assessable) and the decision will be recorded on the Serious Adverse Event form, if necessary with the reasoning of the principal investigator.
 
The assessment of causality is made by the investigator using the following definitions:
 
Relationship to the protocol treatment:
 
UNRELATED - There is no evidence of any causal relationship to the protocol treatment.
 
LIKELY RELATED - There is (some) evidence to suggest a causal relationship to the protocol treatment and influence of other factors is unlikely or absent.
 
NOT ASSESSABLE - There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship to the protocol treatment.
 
Details should be documented on the specified Serious Adverse Event Form.
 
PLEASE FAX THE REPORT TO:
 
Lymphoma Trials Office
CR UK and UCL Cancer Trials Centre
Fax No.+44 (0) 207 679 9861
 
All unexpected SADR reports and all reports involving expected SADR that are life threatening or caused death will additionally be forwarded to all participating investigators. Upon receipt of a safety report from the Lymphoma Trials Office, it is the responsibility of the principal investigators to notify co-investigators.
 
To enable the Lymphoma Trials Office to comply with regulatory reporting requirements, completed documentation of any reported serious adverse events or serious adverse drug reactions must be returned within 10 calendar days of the initial report. If the completed form is not received within this deadline, the Safety Desk will make a written request to the investigator. PLEASE SEND THE ORIGINAL REPORT TO:
 
Watch and Wait
Lymphoma Trials Office
CR UK and UCL Cancer Trials Centre
222 Tottenham Court Road, London W1T 4TJ
 
Tel  +44 (0) 20 7679 9860 
Fax +44 (0) 20 7679 9861
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ALL FORMS MUST BE DATED AND SIGNED BY THE RESPONSIBLE INVESTIGATOR OR ONE OF HIS/HER AUTHORIZED STAFF MEMBERS.
 
17. Reasons to stop the protocol treatment
 
1. Excessive toxicity that does not allow the protocol treatment to be given.
2. Significant disease progression requiring systemic chemotherapy or radiotherapy.
3. Patient choice.
4. Investigator’s decision that the protocol treatment is not anymore in the best interest of the patient.
 
18. Statistical considerations
 
a. Sample size
The number of patients required assumes that the median time until initiation of chemotherapy will be 30 months in the Watch and Wait arm. The trial is designed to detect an improvement in the median time to initiation of therapy in the rituximab arm of 18 months (a hazard ratio of 0.625) with a 5% significance level and 90% power. 192 events (initiation of therapy) are required. To observe this required number of events, we plan to accrue 360 patients (180 in each arm) during 4 years and have a further 2 years follow-up after the last patient is entered.
 
b. Planned analyses
Analyses will be performed on an intention-to-treat basis. The standard log-rank test will be applied to time-to-event outcome analyses along with plots of Kaplan-Meier curves. The c2 test or Mann-Whitney test will be implemented in the comparisons on categorical outcomes. Subgroup analyses will be performed according to age, stage, grade of disease, and Follicular Lymphoma International Prognostic Index (FLIPI)15 in an exploratory manner.
 
c. Data monitoring and ethics committee (DMEC)
An independent DMEC will meet soon after the start of accrual to draw to draw up guidelines for examining trial data and for advising on the trial’s progress and continuation. It is anticipated that this DMEC will meet at approximately yearly intervals; the exact frequencies will depend upon accrual, progression and death rates. At the first meeting the DMEC will advise on the nature and frequency of the subsequent interim analyses. The interim analyses will be performed by a statistician at the Lymphoma Trials Office and will be confidential unless the DMEC advises otherwise. The members of the DMEC will write an annual report with recommendations to the Trial Steering Committee.
 
d. Trial steering committee (TSC)
The role of the TSC is to provide overall supervision of the trial and to ensure that the trial is conducted in accordance with GCP. This independent committee will review the recommendations from the DMEC. On consideration of this information, the TSC will decide on continuing or stopping the trial, or modifying the protocol.
 
19. Quality assurance
 
The Lymphoma Trials Office will be responsible for reviewing the protocol, collecting case report forms, controlling the quality of the reported data, and generating reports and analyses in co-operation with the Study Coordinator. All methodological questions should be addressed to:
 
 
 
Watch and Wait Trial Coordinator
Lymphoma Trials Office,
Cancer Research UK and UCL Cancer Trials Centre,
90 Tottenham Court Road, London W1T 4TJ.
Tel:  +44 (0) 20 7679 9868 , Fax: +44 (0) 20 7679 9861
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Control of data consistency
Data forms will be entered in the database of the Lymphoma Trials Office. Computerised and manual consistency checks will be performed on newly entered forms; queries will be issued in case of inconsistencies. Consistent forms will be validated by the Data Manager to be entered on the master database. Inconsistent forms will be kept "pending" until resolution of the inconsistencies.
 
External review of histology
In order to assure the high quality and consistent pathology diagnosis, a centralised pathology review is included in this trial. Each country will have an appointed histopathologist responsible for central review.In the United Kingdom the appointed histopathologist is Dr Andrew Jack, Consultant Histopathologist, Haematological Malignant Diagnosis Service.
 
Within two weeks from the date of registration, the local pathologist must send to the central pathologist the following material:
·                paraffin block(s) or thirteen (13) unstained slides (paraffin blocks are preferred & will be returned)
·                the original pathology form (only the local pathology part should be completed)
 
For UK centres, please send the samples to:
 
Lymphoma Trials Office
CR UK and UCL Cancer Trials Centre
90 Tottenham Court Road, London W1T 4TJ
United Kingdom
 
[Separate arrangements to be agreed for non U.K. patients]
 
The final diagnosis of the Central Pathologists will be considered as definitive for the trial.
The diagnosis made by the local pathologist of the participating centre will be accepted for the registration.
 
 
 
 
 
20. Ethical considerations
 
Patient protection
The responsible investigator will ensure that this study is conducted according to guidelines for Good Clinical Practice. The protocol will by approved by a Multi-Centre Research Ethics Committee (MREC).
 
Subject identification
The name of the patient will not be asked for nor recorded at the Data Centre. A sequential identification number will be automatically attributed to each patient registered in the trial. This number will identify the patient and must be included on all case report forms. In order to avoid identification errors, patient’s initials (maximum of 4 letters), date of birth and local hospital number (if available) will also be reported on the case report forms.
 
Informed consent
All patients will be informed of the aims of the study, the possible adverse events, the procedures and possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. They will be informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by authorized individuals other than their treating physician.
The informed consent form is part of the documents to be submitted to the MREC ethics committee for approval. Local informed consent forms may require validation by local research and development departments, according to local practice.
 
It will be emphasized that participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. Documented informed consent must be obtained for all patients included in the study before they are registered or randomised at the data centre. The written informed consent form must be signed and personally dated by the patient. This must be done in accordance with the national and local regulatory requirements. 
 
Specific consent will be sought for the use of DNA extracted from blood and bone marrow to be used by future researchers investigating factors involved in the pathogenesis of lymphoma and factors which determine response to treatment. The nature of these studies has not yet been defined. All proposals for the use of this genetic material will need prior approval by an ethical committee. Patients are able to participate in this clinical research study but not agree to the use of their genetic material in this way.
21. Publication policy
 
The final publication will be written by the study chairman and co-chairman on the basis of the final analyses performed at the CR UK and UCL Cancer Trials Centre. Authors will include the study chairmen and co-chairman, the investigators who have included ≥10% of the eligible patients in the trial, the central data manager and statistician in charge of the trial, the pathologist, the molecular biologists, and the QoL study coordinator. The manuscript will only be submitted for publication after review by all the authors and will acknowledge all participating centres.
22. Quality of Life issues (participating countries only)
 
Quality of life assessment
Health related Quality of Life (QoL) is a multidimensional concept reflecting the physiological, psychological and social influences of the disease and the therapeutic process from the patient’s perspective. It comprises four principal components: physical, psychological and social well-being, and daily-life functioning.
 
The quality of life instrument
Patients entered into this trial will be relatively asymptomatic by definition. The QoL instruments must therefore be able to detect changes in well being in this group of patients. In addition the questionnaires will have to measure changes in anxiety and depression. The following questionnaires will be used (See Appendix 2):
 
1) The ‘Functional Assessment of Cancer Therapy (FACT-G)’questionnaire. This consists of questions relating to physical, social/family, emotional and functional well being.
2)            Hospital Anxiety and Depression Scale (HADS)
3)            Impact of Event Scale-Revised (IES-R)
4)            Additional questions relating to lymphoma such as:
a.     I am worried about my disease becoming more aggressive
b.    I am worried about my disease requiring treatment/more treatment
c.     Because of my illness, I have difficulty planning for the future
d.    I worry about being able to support myself or my family due to my illness
5)            Four questions on Illness Coping Style
6)            Five questions from the Illness Impact Bank
7)            Three questions from the Mental Adjustment to Cancer Scale
 
Quality of Life is an integral part of the trial in the UK and will be assessed on all patients entered into the study. The Quality of Life questionnaire is in the English language.
 
Other countries whose national language is not English, and who express a strong preference to join in the QoL study will be able to. The FACT-G and HADS meet the standards for reliability and are valid across different language-cultural groups. All other questions will be made available in the national language of those countries that elect to participate in the Quality of Life component.
 
The Quality of Life component will become an integral part of the trial in both English speaking and non-English speaking countries who, at the start of the trial, elect to participate in this component, and therefore Quality of Life should be assessed in all patients who enter the trial.
 
QoL data collection: where and how
 
QoL questionnaires must be filled out at the hospital when the patients come for a scheduled visit. The questionnaire should be handed out to the patients by the investigator or a study nurse prior to seeing the doctor for clinical evaluations. Patients should be asked to fill out the questionnaires in confidence as completely and accurately as possible. The average time to complete the entire questionnaire is approximately 10-15 minutes. Ideally the completed forms should be returned to the medical team in a sealed pre-labelled envelope, which should be posted to the coordinating centre.
 
QoL data collection – timing
 
1.   A baseline questionnaire must be completed prior to randomisation but after informed consent has been obtained.
2.   The patient should complete another questionnaire after they have been informed about which arm they have been allocated to but prior to receiving any treatment. Ideally the patient should have been aware of their allocation for at least one week. This dual pre treatment questionnaire design is to evaluate whether the impact of treatment assignment on health related quality of life responses.
3.   A questionnaire should be completed subsequently at each 2 monthly clinic visit for the first 2 years. A time window of ± 2 weeks around the scheduled assessment point will be acceptable.
4.    Subsequently questionnaires should be completed every 6 months for the following 2 years. A time window of ± 4 weeks around the scheduled assessment point will be acceptable.
 
QoL follow up will cease after 4 years from randomisation as the median time until initiation of treatment in W and W arm is 32 months.
 
Quality of life co-ordinator
 
Missing data hampers assessment of QoL in clinical trials. The major cause of missing data is because centres do not administer the questionnaires at the appropriate time (unit non-response), rather than patients missing questions within the questionnaires (item non-response), which usually accounts for less than 2% and therefore is rarely a problem.
 
It is anticipated that participating countries will need to appoint a Quality of Life coordinator.
The role of this person will to be to:
1)     Establish contact with participating centres at enrolment in order to ensure that clinical teams and research nurses are properly informed and motivated about QoL assessment.
2)     Remind centres to issue questionnaires when patients are due to attend clinic appointments.
3)     Collect and input the QoL data obtained.
 
Statistical Considerations
 
There is little available data on the baseline functional well being or anxiety of this group of patients. However a difference between the 2 treatment arms of 20% at 6 months would be considered clinically significant. Therefore, a range of values is possible, for example:
 
Proportion of patients reporting borderline or case anxiety on the HADS 6 months after randomisation.
Total patients required to reliably detect a 20% decrease in the watch and wait group:
 
Watch and wait   Rituximab group (5% significance level, 90% power)
            30%                 10%                 164 patients     
40%                 20%                 218 patients
50%                 30%                 248 patients
 
The aim therefore will be to accrue at least 220 patients and to monitor the baseline figures after the first 50 patients have been recruited into the QoL study and adjust the sample size accordingly.
 
23. Handling of Blood and Bone marrow samples for pcr
 
It is important that the first 2-3 mls of bone marrow aspirated should be collected for DNA and RNA extraction. This should be added to EDTA. 20-30 ml of blood should also be collected into EDTA.
Samples should ideally be taken in the early part of the week (Monday to Wednesday preferably) and sent by first class post/guaranteed next day delivery if possible.
Details of where non-UK samples should be sent will be arranged by the coordinating centre for that country. Samples from the UK should be sent to:
 
Haematology and Blood Transfusion
UCLH
For the attention of Yashma Patel
2nd floor, 60 Whitfield St
London W1T 4EU
United Kingdom
 

23. References
1.         Portlock CS, Rosenberg SA (1979)
No initial therapy for Stage III and IV non-Hodgkin’s Lymphomas of favourable histological types.
Ann Int Med 90: 10-13.
 
2.         Horning SJ and Rosenberg SA (1984)
The natural history of initially untreated low-grade non-Hodgkin’s Lymphoma. NEJM 311: 1471 – 1475.
 
3.   Young et al 1998
The treatment of indolent lymphomas: watchful waiting versus aggressive combined modality treatment. Sem Haematol 25: 11-16.
 
4.         Brice et al 1997
Comparison in low tumour-burden follicular lymphomas between an initial no-treatment policy, prednisolone or interferon alpha: a randomised study from GELF. J. Clin Oncol 15: 1110-1117
 
5.         O'Brien et al 1991
The natural history of low grade non-Hodgkin's lymphoma and the impact of a no initial treatment policy on survival. Q J Med 80(292): 651-60.
 
6.         Ardeshna K. et al 2003
Long term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced stage non-Hodgkin’s lymphoma: a randomised controlled trial. The Lancet 2003 362 p516-22
 
7.         Freedman et al 1999
Long term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94: 3325-33
 
8.         Attal et al 1997
Allogeneic bone marrow transplantation for refractory and recurrent follicular lymphoma: a case matched analysis with autologous transplantation form the French bone marrow transplant group registry data. Blood 90 (Suppl. 1) 255a
 
9.   Khouri et al 2001
Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma : low incidence of toxicity, acute GVHD and treatment related mortality. Blood 98: 3595-3599
 
10.       Czuczman et al 2001
Progression free survival after six years follow up of the first clinical trial of Rituximab/CHOP chemoimmunotherapy. Blood 98 (11) 2519a.
 
11.       McLaughlin P et al 1998
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma : half of patients responded to a four dose treatment program. J. Clin Oncol 16 : 2825-2833
 
12.       Solal-Celigny P 2001
Rituximab as first-line immunotherapy in low-grade follicular lymphoma with a low tumour burden.
Anti Cancer Drugs 12 (Suppl 2) 511-514.
 
13.       Cheson et al 1999
Report on an international workshop to standardise response criteria for non-Hodgkin’s lymphomas. JCO 17 (4) 1999 pp 1244-1253
 
14.       F. Hoffmann-La Roche Ltd, 2003 (Eight Edition)
Investigator’s Brochure Ro 45-2294, MabThera, Rituxan, IDEC-C2B8 (Rituximab), Oncology and Hematology
 
15.       Solal-Celigny P.et al 2004
Follicular lymphoma international prognostic index. Blood. 2004; 104: 1258-1265
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