Plain English Summary
Not provided at time of registration
Trial website
Contact information
Type
Scientific
Primary contact
Prof Stephen O'Brien
ORCID ID
Contact details
Freeman Hospital
Freeman Road
High Heaton
Newcastle-upon-Tyne
NE7 7DN
United Kingdom
0191 282 0904
wendy.banks@ncl.ac.uk
Additional identifiers
EudraCT number
2012-005696-14
ClinicalTrials.gov number
Protocol/serial number
A15810
Study information
Scientific title
A phase 3 randomised non-inferiority trial to evaluate the most effective way to use imatinib, nilotinib and ponatinib in patients with newly-diagnosed chronic phase chronic myeloid leukaemia
Acronym
SPIRIT 3
Study hypothesis
To investigate whether first-line treatment with imatinib (group I) is non-inferior to first-line treatment with nilotinib (group N) when patients on either treatment who are not responding optimally switch to ponatinib. Additionally to investigate whether patients who respond well can subsequently have their treatment reduced and eventually stopped with no adverse consequences.
Ethics approval
Ethics committee approval will be sought via IRAS.
Study design
Randomised phase III open label non-inferiority trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
http://spirit3.spirit-cml.org/
Condition
Chronic myeloid leukaemia
Intervention
1. Imatinib - taken as a once daily medication at a dose of 400mg in tablet format. 400mg and 100mg tablets are available to allow dose adjustment.
2. Nilotinib - taken as a twice daily medication at a dose of 300mg (600mg total daily dose) in tablet format. 200mg and 150mg tablets are available to allow dose adjustment.
3. Ponatinib - taken as a once daily medication at a dose of 45mg in tablet format. Ponatinib is supplied as 15mg tablets to allow dose adjustment.
Patients who are eligible will be randomised to receive either imatinib 400mg (Group I) or nilotinib 600mg (300mg BID) (Group N). The treatment allocation will be prepared by the trial statistician and based on a 1:1 ratio between the two arms. Patients who do not respond optimally to these treatments will be switched to ponatinib. Subsequently patients who have received a minimum of 3 years TKI treatment and who have achieved MR3 (BCR-ABL/ABL ratio of 0.1% or less) on any treatment combination and then maintain MR3 or better for a minimum of 2 years will have opportunity to reduce their TKI dose for 12 months and then subsequently cease TKI treatment altogether.
Patients will be followed up and assessed at the time points outlined in the following Assessment Schedules
1. Schedule - S (Screening/Baseline Schedule) All patients
2. Schedule T (Randomised Treatment) Stage 1 - All Patients
3. Schedule - P (Ponatinib Treatment) Stage 2 Switching patients only
4. Schedule - R (Dose Reduction and Stopping) Stage 3 Eligible patients only
5. Schedule FU (Off Study Treatment Follow-up) Patients who have permanently discontinued study drug before the end of the study.
Intervention type
Drug
Phase
Phase III
Drug names
Imatinib, nilotinib, ponatinib
Primary outcome measure
To determine whether, in terms of major molecular response (MMR, MR3) at three years, first-line treatment with imatinib is non-inferior to first-line treatment with nilotinib when patients on either treatment who are not responding optimally switch to ponatinib.
Secondary outcome measures
1. To assess survival (OS, PFS and EFS) in group I vs group N at 5 years from study entry.
2. To determine what proportions of patients in group I and in group N who have been on study for at least 3 years and who have achieved stable MR3 for at least 2 years can reduce or stop TKI treatment and maintain at least MR3.
3. To compare the cost effectiveness over a 5 year period (and projected over the lifetime of the patient) of group I vs group N.
Overall trial start date
01/09/2013
Overall trial end date
01/09/2023
Reason abandoned (if study stopped)
Lack of funding/sponsorship
Eligibility
Participant inclusion criteria
1. Male or female patients who are 18 years of age or over.
2. Patients must fulfill all of the following:
2.1. Be diagnosed with chronic phase chronic myelogenous leukemia (CML) confirmed by blood morphology and reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL.
2.2. Be enrolled within 3 months of initial diagnosis of chronic phase CML (date of RT-PCR confirming presence of BCR-ABL)
2.3. Be in confirmed chronic phase ie:
2.3.1. Less than 15% blasts in blood (manual differential)
2.3.2. Less than 30% blasts plus promyelocytes in blood
2.3.3. Less than 20 % basophils in blood
2.3.4. Less than 100 x 109 /L platelets
2.3.5. No evidence of extramedullary leukaemic involvement, with the exception of hepatosplenomegaly
3. Written voluntary informed consent.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
1000
Participant exclusion criteria
1. Any prior treatment for CML with any tyrosine kinase inhibitors (TKI) (eg imatinib, dasatinib, nilotinib, bosutinib, ponatinib); busulphan, interferon-alpha (IFN-alpha), homoharringtonine, cytosine arabinoside, any other investigational agents.
2. Patients who have received prior CML chemotherapy including regimens used in peripheral blood progenitor cells (PBPCs) mobilisation for haematopoietic progenitor-cell transplantation. (collection of unmobilised PBPCs is allowed at diagnosis).
3. Patients who have had any form of prior haematopoietic stem cell transplant (autograft or allograft).
4. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≥ 3
5. Patients with serum bilirubin, SGOT/AST, SGPT/ALT or creatinine concentrations > 2.0 x upper limit of normal (ULN)
6. Patients with serum amylase or lipase > 1.5 x ULN, history of acute pancreatitis within 1 year of study, history of chronic pancreatitis, or uncontrolled hypertriglyceridaemia (triglycerides > 450 mg/dL)
7. Patients with significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to a) myocardial infarction, unstable angina and/or congestive heart failure within 6 months prior to study; and b) history of clinically significant atrial arrhythmia; or any ventricular arrhythmia.
8. Patients taking medications known to be associated with Torsade de Pointes (eg amiodarone, azithromycin, chloroquine, citalopram, domperidone, erythromycin, quinidine, sotalol, thioridazine)
9. Patients with known uncontrolled hypertension; systolic blood pressure > 140mm Hg and/or diastolic blood pressure > 90mm Hg
10. Patients with a known international normalized ratio (INR) or partial thromboplastin time (PTT) > 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants, or patients with a known bleeding disorder. Baseline testing of INR is not required.
11. Patients with uncontrolled medical disease such as diabetes mellitus, thyroid dysfunction, neuropsychiatric disorders or infection.
12. Patients who have undergone major surgery within 4 weeks of starting trial investigational medicinal products (IMP).
13. Patients who are:
13.1. Pregnant
13.2. Breast feeding
13.3. Of childbearing potential without a negative pregnancy test prior to starting trial IMP
13.4. Male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential).
14. Patients with a history of another malignancy either currently or within the past five years (with the exception of basal cell skin carcinoma in situ).
15. Patients with a history of non-compliance to medical regimens or patients who can envisage being unable to complete the study for any reason.
16. Patients unwilling to receive trial drug via a home delivery method.
Recruitment start date
01/09/2013
Recruitment end date
01/09/2023
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Freeman Hospital
Newcastle-upon-Tyne
NE7 7DN
United Kingdom
Sponsor information
Organisation
Newcastle-upon-Tyne Hospitals NHS Foundation Trust (UK)
Sponsor details
Freeman Hospital
Freeman Road
High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom
+44 (0)191 282 0904
meg.buckley@ncl.ac.uk
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Industry
Funder name
ARIAD Pharmaceuticals (USA)
Alternative name(s)
Ariad
Funding Body Type
private sector organisation
Funding Body Subtype
corporate
Location
United States of America
Funder name
Cancer Research UK (UK)
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
other non-profit
Location
United Kingdom
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
Basic results (scientific)
Publication list