Imiquimod Trial (Part 2)

Objectives

1. To determine the antibody response rates to subcutaneous vaccination with influenza vaccine in patients with untreated stage A chronic lymphocytic leukaemia.
2. To determine whether subsequent application of Imiquimod cream to the vaccination site will enhance the antibody response.
3. To vaccinate patients’ spouses to control for the subcutaneous route and the older age group to which patients are likely to belong
4. To save samples of blood for subsequent investigation of T cell responses.

Trial Design

This is a randomized phase II study comparing antibody responses to two influenza vaccination protocols in patients with untreated stage A CLL.

Eligibility

All patients with CLL stage A (see BCSH guidelines3) who have not been treated with corticosteroids, chemotherapy or monoclonal antibodies.

Exclusion Criteria

1. Patients with other malignancies
2. Patients receiving corticosteroids or other immunosuppressive drugs
3. Patients who have received vaccination against influenza in the past 6 months
4. Patients who have had an allergic reaction to a flu shot in the past, or have an allergy to eggs or who previously developed Guillain-Barré syndrome within 6 weeks of getting a flu shot
5. Patients failing to give informed consent.

List of Recommended Investigations

1. Prior to vaccination: FBC, urea and electrolytes, liver functions studies, serum immunoglobulins.
2. Prior to vaccination: in patients who have not previously be tested for prognostic factors: IgVH mutations, CD38, ZAP-70, FISH for del11q and del 17p.
3. Prior to vaccination: serum sample for antibodies to influenza haemagglutinins.
4. Prior to vaccination: 50mls whole blood for future T cells studies.
5. 28 days post vaccination: serum sample for antibodies to influenza haemagglutinins
6. 14 days post vaccination: 50 ml whole blood for future T cells studies.


How Investigations will be carried out

Routine blood counts and biochemistry will be carried out at the laboratories of the Royal Bournemouth Hospital. Samples for T cells testing will be separated and frozen down for future study. We expect to receive future funding to carry out these investigations in house. These will comprise Elispot tests to investigate specific release of cytokines from T cells.

Samples for haemagglutination inhibition titres against influenza H1N1, H2N3, and B antigens will be batched and frozen, and tested under contract by the Central Public Health Laboratory Specialist & Reference Microbiology Division, 61, Colindale Avenue, London NW9 5HT.

Vaccination procedure


Vaccination will use the 2006--07 trivalent influenza vaccine virus strains: A/New Caledonia/20/1999 (H1N1)-like, A/Wisconsin/67/2005 (H3N2)-like, and B/Malaysia/2506/2004-like antigens. For the A/Wisconsin/67/2005 (H3N2)-like antigen, the vaccine may contain instead the antigenically equivalent A/Hiroshima/52/2005 virus; for the B/Malaysia/2506/2004-like antigen, the vaccine may contain the antigenically equivalent B/Ohio/1/2005 virus.

0.5 ml of the vaccine will be administered subcutaneously under the skin over the deltoid muscle. A two cm diameter circle will be drawn on the skin around the injection site in water insoluble ink

Those patients randomized to receive Imiquimod will be instructed to rub a small amount Imiquimod cream into the skin within the circle, starting on the day after the vaccination and continuing daily for five days. Imiquimod comes in a sachet that can be sealed by a paper clip, and should be kept refrigerated between applications. The cream should be left on the skin for 8 hours and then washed off with soap and water.

Patients’ spouses will be offered vaccination and if they consent they will receive subcutaneous vaccination in the same way as the patients, but they will not receive application of the Imiquimod cream.

Side effects

Imiquimod is licensed for application to genital skin. It can produce local erythema with itching and pain with prolonged use. A single application is likely to produce nothing more than mild local inflammation.

Influenza vaccines are produced in the allantoic cavity of chick embryos and are therefore contraindicated in those with allergy to eggs. Otherwise, mild local inflammation and mild ‘flu like symptoms are the most likely side effects.

Source of patients for study

There are currently just over 100 untreated stage A CLL patients attending out-patient clinics at the Royal Bournemouth Hospital who have had blood tested for prognostic markers. It is from this group of patients that subjects for the study will initially be recruited. If insufficient patients can be recruited from the study from this cohort, patients who have not had prognostic markers studied will be invited to participate. Prognostic markers will be determined for this group.


Randomization

Randomization will be achieved by opening a series of numbered sealed envelopes kept in the office of the Haematology secretariat. The envelopes will contain a card on which is written A or B; computer generated random numbers will determine which, A for even numbers, B for odd numbers.

Statistical Calculations

Assuming that the control group has a 15% response to vaccination, an improvement to a 50% response rate would be worthwhile. To have an 90% chance of detecting such an improvement at the p=5% level would require 34 patients in each arm.

Evaluation

Response to vaccination is defined as a fourfold increase in haemagglutination inhibition titre. A haemagglutination inhibition titre of 100 is regarded as protective. Results will be compared between the two arms of the study. Responses to vaccination will be compared with several other factors, including age, sex, presence or absence of palpable lymph nodes and spleen, serum immunoglobulin levels, prognostic factors and length of time the patient has been diagnosed for.

Ethical Considerations

Prior to starting the study, the protocol must be approved by Local Research and Ethical Committee (LREC). Amendments to the protocol may only be made with approval by the Principal Investigator, and will be subject to review by the LREC. Written documentation of the Ethics Committee approval must be received before the amendment can be incorporated into the protocol.

The patient will be given time to discuss his/her participation in the study with the Investigator concerned and family members as well as his or her GP. Before the patient is entered into the study, the patient’s written consent must be obtained. A copy will be retained by the patient and the original filed in the Investigator's Trial File unless otherwise agreed.

The patient may refuse treatment either before or at any time during the study. Refusal to participate will involve no penalty or loss of benefits to which the patient is otherwise entitled.

The study will be carried out in accordance with the Declaration of Helsinki.

Suspected Unexpected Serious Adverse Events (SUSARs)

An adverse reaction is ‘serious’ if it:
a. results in death;
b. is life-threatening;
c. requires hospitalization or prolongation of existing hospitalization;
d. results in persistent or significant disability or incapacity;
e. consists of a congenital anomaly or birth defect.
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the information about the medicinal product in question set out:
a. in the case of a product with a marketing authorization, in the summary of product characteristics for that product;
b. in the case of any other investigational medicinal product, in the investigator’s brochure relating to the trial in question.

A SUSAR which is fatal or life-threatening must be reported to the LREC as soon as possible and in any event within seven days after the sponsor became aware of the event. Any additional information must be reported within eight days of sending the first report.
A SUSAR which is not fatal or life-threatening must be reported to the LREC as soon as possible and in any event within 15 days after the sponsor became aware of the event.

Publication policy

Results of this study will be submitted for publication.