Condition category
Cancer
Date applied
21/01/2011
Date assigned
21/01/2011
Last edited
18/12/2015
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Mr Scott Regan

ORCID ID

Contact details

Clinical Trials Unit
MP131
Tremona Road
Southampton
SO16 6YD
United Kingdom
+44 2380 794307
s.e.regan@soton.ac.uk

Additional identifiers

EudraCT number

2009-017340-14

ClinicalTrials.gov number

NCT01334060

Protocol/serial number

7339; EME 08/99/24

Study information

Scientific title

WT1 immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a multicentre interventional treatment open label single dose phase II study using genetic randomisation

Acronym

WIN trial

Study hypothesis

Open label, single dose level, phase II study in two patient groups (CML and AML) using genetic randomisation. Consented and eligible HLA A2+ve patients will be vaccinated with two DNA vaccines and HLA A2 -ve patients will be followed up with molecular monitoring only.

The objectives are to evaluate:
1. Molecular response following p.DOM-epitope DNA vaccination in patients with CML (BCR-ABL, WT1) and AML (WT1) at weeks 4, 8, 12, 16, 20 and at months 6, 12, 18 and 24
2. Time to disease progression, 2 year survival rate (patients with AML)
3. Correlation of molecular responses with immunological responses

Primary objective:
CML: Molecular response of BCR-ABL
AML: Time to disease progression

Secondary objective:
Molecular response of WT1 transcript levels, immune responses to WT1 and DOM, Toxicity, CML-Time to disease progression, next treatment and survival, AML-2 year survival, overall survival.

Ethics approval

Gene Therapy Advisory Committee (GTAC) approved on 15/11/2010 (ref: 173)

Study design

Multicentre randomised interventional treatment open label single dose phase II study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Topic: National Cancer Research Network; Subtopic: Haematological Oncology; Disease: Leukaemia (acute), Leukaemia (chronic), Leukaemia (acute myeloid), Leukaemia (acute lymphoblastic), Leukaemia (acute promyelocytic)

Intervention

Current interventions as of 22/12/2011

Patients that are HLA A2+ will receive both vaccines as per below:

1. p.DOM-WT1-37:
Dosage: 1 mg
Method: intramuscular electroporation
Frequency of administration: 6 times at 4 weekly intervals - Responders (immunological but without molecular progression) may continue vaccination 3 monthly
Total duration of treatment: maximum of 24 months
Follow-up: 24 months post treatment

2. p.DOM-WT1-126:
Dosage: 1 mg
Method: intramuscular electroporation
Frequency of administration: 6 times at 4 weekly intervals - Responders (immunological but without molecular progression) may continue vaccination 3 monthly
Total duration of treatment: maximum of 24 months
Follow-up: 24 months post treatment

Patients that are HLA A2- will be monitored as the control group.

Measured in vaccinated patients only:
1. Autoimmune profile (together with other blood tests)
2. Bone marrow aspirate (all patients except HLA A2 negative CML patients)
3. Electrocardiogram (ECG), 1 before and after each vaccination
4. Immunological samples, samples for immunological analysis, blood (together with other blood tests)
5. Leukophoresis
6. Serum electrophoresis (together with other blood tests)
7. Skin biopsies (to be carried out if wherever feasible)

Measured in all patients:
8. Full blood count, biochemistry, (together with other blood tests)
9. Clotting (together with other blood tests)
10. HLA A2 test (together with other blood tests)
11. Infectious disease screen (human immunodeficiency virus [HIV], syphilis, Hepatitis, HTLV, CMV) (together with other blood tests)
12. Quantitative polymerase chain reaction (qPCR) (together with other blood tests)

Measured routinely:
13. Chest X ray


Previous interventions

Patients that are HLA A2+ will receive both vaccines as per below:

1. p.DOM-WT1-37:
Dosage: 1 mg
Method: intramuscular electroporation
Frequency of administration: 6 times at 4 weekly intervals - Responders (immunological but without molecular progression) may continue vaccination 3 monthly
Total duration of treatment: maximum of 24 months
Follow-up: 24 months post treatment

2. p.DOM-WT1-126:
Dosage: 1 mg
Method: intramuscular electroporation
Frequency of administration: 6 times at 4 weekly intervals - Responders (immunological but without molecular progression) may continue vaccination 3 monthly
Total duration of treatment: maximum of 24 months
Follow-up: 24 months post treatment

Patients that are HLA A2- will be monitored as the control group.

Measured in vaccinated patients only:
1. Autoimmune profile (together with other blood tests)
2. Bone marrow aspirate
3. Electrocardiogram (ECG), 1 before and after each vaccination
4. Immunological samples, samples for immunological analysis, blood (together with other blood tests)
5. Leukophoresis
6. Serum electrophoresis (together with other blood tests)
7. Skin biopsies

Measured in all patients:
8. Full blood count, biochemistry, (together with other blood tests)
9. Clotting (together with other blood tests)
10. HLA A2 test (together with other blood tests)
11. Infectious disease screen (human immunodeficiency virus [HIV], syphilis, Hepatitis, HTLV, CMV) (together with other blood tests)
12. Quantitative polymerase chain reaction (qPCR) (together with other blood tests)

Measured routinely:
13. Chest X ray

Intervention type

Drug

Phase

Phase II

Drug names

p.DOM-epitope DNA vaccination

Primary outcome measures

1. CML: Molecular response of BCR-ABL transcripts, measured at any time during follow up
2. AML: time to disease progression

Secondary outcome measures

1. AML: 2-year survival, overall survival, measured at any point during follow up
2. AML: Time to disease progression, measured at any point during follow up
3. Molecular response of WT1 transcripts, measured at any point during follow up

Overall trial start date

30/11/2010

Overall trial end date

31/07/2012

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 02/07/2012

1. CML group:
1.1. Philadelphia chromosome positive CML in chronic phase
1.2. In complete cytogenetic response (CCyR) but with detectable BCR-ABL transcripts and maintained the CCyR on Imatinib monotherapy for a minimum of 24 months

2. AML group:
2.1. WT1+ AML in CR or morphologic CR with incomplete blood count recovery (CRi)
As the vast majority of AML express WT and evaluation in CR or CRi is technically not feasible, formal demonstration of WT1 expression in AML cells is not required. Where historical or relapsed samples become available, WT1 expression status will be evaluated post hoc.

3. All patients:
3.1. ≥ 18 years of age, written informed consent
3.2. Performance status of 0 or 1.
3.3. for vaccination groups: HLA-A0201 positive in at least one allele
3.4. for control groups: HLA A2 negative in both alleles
3.5. renal function and liver function (Creatinine <1.5 x upper limit of normal, liver function tests < 1.5 x upper limit of normal); Lymphocyte count > 1.0 x109/l*; normal clotting
3.6. HB>100 g/l
3.7. Adequate venous access for repeated blood sampling according to protocol schedule.
3.8. If sexually active and possibly fertile, patients must agree to use appropriate contraceptive methods during the trial and for six months afterwards.

* If the lymphocyte count is below 1.0 at the time of entry into the trial but has been over 1.0 in the last 6 months and has also not declined rapidly in the days and weeks preceding entry, then the patient is eligible.

Previous inclusion criteria

1. CML group:
1.1. Philadelphia chromosome positive CML in chronic phase
1.2. In complete cytogenetic response (CCyR) but with detectable BCR-ABL transcripts and maintained the CCyR on Imatinib monotherapy for a minimum of 24 months

2. AML group:
2.1. WT1+ AML in CR or morphologic CR with incomplete blood count recovery (CRi)
As the vast majority of AML express WT and evaluation in CR or CRi is technically not feasible, formal demonstration of WT1 expression in AML cells is not required. Where historical or relapsed samples become available, WT1 expression status will be evaluated post hoc.

3. All patients:
3.1. Male and female, lower age limit of 18 years
3.2. Written informed consent
3.3. Performance status of 0 or 1
3.4. For vaccination groups: HLA-A0201 positive in at least one allele
3.5. For control groups: HLA A2 negative in both alleles
3.6. Renal function and liver function (creatinine less than 1.5 x upper limit of normal, liver function tests less than 1.5 x upper limit of normal); lymphocyte count greater than 1.0 x 10^9/l; normal clotting
3.7. HB greater than 100 g/l
3.8. Adequate venous access for repeated blood sampling according to protocol schedule
3.9. If sexually active and possibly fertile, patients must agree to use appropriate contraceptive methods during the trial and for six months afterwards

Previous inclusion criteria

1. CML group:
1.1. Philadelphia chromosome positive CML in chronic phase
1.2. In complete cytogenetic response (CCyR) but with detectable BCR-ABL transcripts and maintained the CCyR on Imatinib monotherapy for a minimum of 24 months

2. AML group:
2.1. WT1+ AML in CR or morphologic CR with incomplete blood count recovery (CRi)

3. All patients:
3.1. Male and female, lower age limit of 18 years
3.2. Written informed consent
3.3. Performance status of 0 or 1
3.4. For vaccination groups: HLA-A0201 positive in at least one allele
3.5. For control groups: HLA A2 negative in both alleles
3.6. Renal function and liver function (creatinine less than 1.5 x upper limit of normal, liver function tests less than 1.5 x upper limit of normal); lymphocyte count greater than 1.0 x 10^9/l; normal clotting
3.7. HB greater than 100 g/l
3.8. Adequate venous access for repeated blood sampling according to protocol schedule
3.9. If sexually active and possibly fertile, patients must agree to use appropriate contraceptive methods during the trial and for six months afterwards

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned sample size: 184

Participant exclusion criteria

1. CML patients:
1.1. CML in accelerated phase or blast crisis or having achieved CMR at any point during imatinib therapy
1.2. Imatinib dose modification in the previous year, imatinib interruption for more than 15 days in the previous 6 months to enrolment
1.3. Prior interferon-a therapy
1.4. Hypocellular bone marrow (less than 20%) (indicated by blood counts and most recent bone marrow (where available)
1.5. Complete molecular response (CMR)

2. AML patients:
2.1. AML in haematological relapse or eligible for allogeneic SCT
2.2. Hypocellular bone marrow (less than 20%)
2.3. AML patients with the "good-risk" abnormalities comprised by the core binding factor leukaemias (i.e., AML with the translocation [8;21] and inversion of chromosome 16, and acute promyelocytic leukaemia with the translocation [15;17])
3. All patients:
• ≥ 18 years of age, written informed consent
• Performance status of 0 or 1.
• for vaccination groups: HLA-A0201 positive in at least one allele
• for control groups: HLA A2 negative in both alleles
• renal function and liver function (Creatinine <1.5 x upper limit of normal, liver function tests < 1.5 x upper limit of normal); Lymphocyte count > 1.0 x109/l*; normal clotting
• HB>100 g/l
• Adequate venous access for repeated blood sampling according to protocol schedule.
• If sexually active and possibly fertile, patients must agree to use appropriate contraceptive methods during the trial and for six months afterwards.

* If the lymphocyte count is below 1.0 at the time of entry into the trial but has been over 1.0 in the last 6 months and has also not declined rapidly in the days and weeks preceding entry, then the patient is eligible.

Previous exclusion criteria as of 22/12/2011

1. CML patients:
1.1. CML in accelerated phase or blast crisis or having achieved CMR at any point during imatinib therapy
1.2. Imatinib dose modification in the previous year, imatinib interruption for more than 15 days in the previous 6 months to enrolment
1.3. Prior interferon-a therapy
1.4. Hypocellular bone marrow (less than 20%) (indicated by blood counts and most recent bone marrow (where available)
1.5. Complete molecular response (CMR)

2. AML patients:
2.1. AML in haematological relapse or eligible for allogeneic SCT
2.2. Hypocellular bone marrow (less than 20%)
2.3. AML patients with the "good-risk" abnormalities comprised by the core binding factor leukaemias (i.e., AML with the translocation [8;21] and inversion of chromosome 16, and acute promyelocytic leukaemia with the translocation [15;17])

3. All patients:
3.1. Systemic steroids or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry
3.2. Major surgery in the preceding three to four weeks from which the patient has not yet recovered
3.3. Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection
3.4. Patients with any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease
3.5. Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study.
3.6. Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing.

Previous exclusion criteria

1. CML patients:
1.1. CML in accelerated phase or blast crisis or having achieved CMR at any point during imatinib therapy
1.2. Imatinib dose modification in the previous year, imatinib interruption for more than 15 days in the previous 6 months to enrolment
1.3. Prior interferon-a therapy
1.4. Hypocellular bone marrow (less than 20%)
1.5. Complete molecular response (CMR)

2. AML patients:
2.1. AML in haematological relapse or eligible for allogeneic SCT
2.2. Hypocellular bone marrow (less than 20%)
2.3. AML patients with the "good-risk" abnormalities comprised by the core binding factor leukaemias (i.e., AML with the translocation [8;21] and inversion of chromosome 16, and acute promyelocytic leukaemia with the translocation [15;17])

3. All patients:
3.1. Systemic steroids or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry
3.2. Major surgery in the preceding three to four weeks from which the patient has not yet recovered
3.3. Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection
3.4. Patients with any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease
3.5. Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study.
3.6. Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing.

Recruitment start date

30/11/2010

Recruitment end date

31/07/2012

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Clinical Trials Unit, MP131
Southampton
SO16 6YD
United Kingdom

Sponsor information

Organisation

Southampton University Hospitals NHS Trust (UK)

Sponsor details

Tremona Road
Southampton
SO16 6YD
United Kingdom
+44 23 8047 7414
RandDoffice@suht.swest.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.suht.nhs.uk/home.aspx

Funders

Funder type

Research council

Funder name

Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: EME 08/99/24)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Leukaemia Research Foundation (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes