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Trial registered on ANZCTR


Registration number
ACTRN12612000851864
Ethics application status
Approved
Date submitted
9/08/2012
Date registered
13/08/2012
Date last updated
29/03/2019
Date data sharing statement initially provided
29/03/2019
Date results information initially provided
29/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase II study of nilotinib plus pegylated interferon alfa-2b as first-line therapy in chronic phase chronic myeloid leukaemia aiming to maximize complete molecular response and major molecular response
Scientific title
Phase II study of nilotinib plus pegylated interferon alfa-2b as first-line therapy in chronic phase chronic myeloid leukaemia aiming to maximize complete molecular response and major molecular response
Secondary ID [1] 280966 0
ALLG CML11
Universal Trial Number (UTN)
Trial acronym
Pinnacle, ALLG CML11
Linked study record

Health condition
Health condition(s) or problem(s) studied:
chronic myeloid leukaemia 287077 0
Condition category
Condition code
Cancer 287400 287400 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will commence taking oral nilotinib at 300mg twice daily for 3 months. After 3 months and if nilotinib therapy is tolerated, pegylated interferon-alpha 2b (PEG IFN) will be introduced at a dose of 30micrograms subcutaneously (sc) per week for 4 weeks, then if tolerated, escalated to 50micrograms sc weekly for the remainder of the study
Intervention code [1] 285406 0
Treatment: Drugs
Comparator / control treatment
nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287665 0
To determine the rate of confirmed MR4.5 at 24 months, defined as BCR-ABL quantitative polymerase chain reaction (RQ-PCR) result less than or equal to 0.0032% on 2 successive measurements in patients
Timepoint [1] 287665 0
24 months after commencement of trial
Secondary outcome [1] 298703 0
To determine the proportion of patients achieving MMR, MR4.5 and CMR as a function of time on trial through quantification of BCR-ABL by quantitative polymerase chain reaction (QPCR)
Timepoint [1] 298703 0
12 months
18 months
24 months
Secondary outcome [2] 298704 0
To determine the rate of Complete Cytogenetic Response from the percentage of Ph+ metaphases in bone marrow
Timepoint [2] 298704 0
12 months
Secondary outcome [3] 298705 0
To compare molecular response data from this study (Pinnacle), such as MMR, MR4.5 and CMR rates from BCR-ABL levels to comparable data from frontline CML trials using nilotinib alone.`
Timepoint [3] 298705 0
12 months
Secondary outcome [4] 298706 0
To compare the rate of BCR-ABL mutations detected by QPCR on bone marrow from patients on Pinnacle with the rate of BCR-ABL mutations from patients treated with nilotinib alone on a previous trial
Timepoint [4] 298706 0
12 months
Secondary outcome [5] 298707 0
To determine the tolerability and safety by tabulation of adverse events of nilotinib monotherapy in all patients in the first 3 months of study, and for those patients who persist with nilotinib monotherapy despite discontinuation of pegylated interferon alfa-2b. Adverse event types will be determined as they occur.
Timepoint [5] 298707 0
24 months
Secondary outcome [6] 298708 0
To determine the long term safety of nilotinib specifically with regards to
cardiovascular and peripheral arterial occlusive disease.
Timepoint [6] 298708 0
6 months
12 months
18 months
24 months
Secondary outcome [7] 298709 0
To determine the tolerability and safety of adding Peg-IFN alpha in CML-CP patients treated with nilotinib by tabulation of adverse events. Adverse events will be assessed at regular clinic vists with treating clinican and adverse event types will be determined as they occur.
Timepoint [7] 298709 0
24 months
Secondary outcome [8] 298710 0
To assess overall, transformation-free and progression-free survival (OS, TFS and PFS) of patients on this study. Progression and transformation will be assessed through clinical tests conducted at regular clinic visits.
Timepoint [8] 298710 0
at end of trial
Secondary outcome [9] 298711 0
To test for the existence of an association between the BCR-ABL reading assessed by QPCR at 12 months and achievement of major cytogenetic response assessed by QPCR at 12 months
Timepoint [9] 298711 0
after 12 months of treatment
Secondary outcome [10] 298712 0
To assess patient reported outcomes using the FACT-BRM questionnaire and to compare these surrogate QoL measures between Pinnacle patients and comparable groups of patients treated with TKIs alone
Timepoint [10] 298712 0
0, 3, 6, 12, 24, 36, 48, 60 months
Secondary outcome [11] 298713 0
To test for the existence of an association between each of
(i) dose density of nilotinib; and
(ii) dose density of peg IFN-alpha 2b administration
and the achievement of CMR, MMR and MR4.5; as well as the occurrence of disease transformation and the occurrence of progression through assessments conducted at regular clinic visits
Timepoint [11] 298713 0
at end of trial

Eligibility
Key inclusion criteria
1. Post-pubertal male or female patients aged 18 years or above.
2. Newly diagnosed (within six months of study entry) Ph+ CML-chronic phase with a quantifiable BCR-ABL transcript
3. No prior therapy for CML and no other current anti-leukaemic therapies (other than prior or current treatment with hydroxyurea or anagrelide).
4. No signs of extramedullary leukaemia, except for hepatosplenomegaly.
5. Documented chronic-phase CML as defined by:
i. <15% blasts in both the peripheral blood and bone marrow
ii. <30% blasts and promyelocytes in both the peripheral blood and bone marrow
iii. <20% basophils in the peripheral blood
iv. Platelet count >100 × 10^9/L
6. Eastern cooperative oncology group Performance Status score less than or equal to 2
7. Patients must have the following laboratory values:
a) Potassium level > lower limit of normal (LLN)
b) Calcium (corrected for serum albumin) > LLN
c) Magnesium level > LLN
d) Phosphorus > LLN
e) Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) < 2.5 × upper limit of normal (ULN) or < 5.0 × ULN if considered due to tumour
f) Alkaline phosphatase (ALP) < 2.5 × ULN unless considered due to tumour
g) Bilirubin < 1.5 × ULN unless due to Gilbert’s syndrome
h) Creatinine < 1.5 × ULN
i) Amylase and lipase < 1.5 × ULN
8. a) Female patients of childbearing potential must have a negative serum pregnancy test within one week prior to study entry OR have been amenorrhoeic for at least 12 months.
b) All patients of reproductive potential must agree to use birth control for the duration of the study. This is only required for as long as the patient has reproductive potential. The type of birth control is a decision which should be made between the treating clinician and the patient.
9. Life expectancy of more than 12 months.
10. Patient has given written, informed consent to participate in the study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who have previously received radiotherapy to >25% of their bone marrow.
2. Patients who have undergone major surgery within the 4 weeks prior to study entry or have not recovered from earlier surgery.
3. Impaired cardiac function, including any of the following:
a. Inability to monitor the QT/QTcorrected interval on electrocardiogram (ECG)
b. Long QT syndrome or a known family history of long QT syndrome.
c. Resting bradycardia (<50 beats per minute) suspected to be secondary to cardiac pathology
d. Qt interval corrected (QTc) > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
e. Myocardial infarction within 12 months prior to starting study
f. Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)
g. History of or presence of clinically significant ventricular or atrial tachyarrhythmias
4. Treatment with agents (other than warfarin) that prolong QT interval or inhibit CYP3A4, unless judged to be clinically essential.
5. Another primary malignant disease, except for such conditions that do not currently require treatment, lesions that can be or had been completely excised (eg Skin Cancers) and neoplasms that does not significantly affect long term survival of the patient
6. Significantly impaired gastrointestinal (GI) function or GI disease that may alter nilotinib absorption.
7. Other concurrent uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol.
8. History of confirmed acute or chronic pancreatitis.
9. Cytopathologically confirmed central nervous system (CNS) infiltration. [In the absence of suspicion of CNS involvement, lumbar puncture is not required.]
10. Patients unwilling or unable to comply with protocol and patients with a history of noncompliance or inability to grant informed consent.
11. Known diagnosis of human immunodeficiency virus (HIV) infection.
12. Prior allogeneic stem cell transplantation
13. Patients who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Male and female patients of childbearing potential must agree to employ an effective method of birth control throughout the study and for up to 3 months following discontinuation of study drug; The type of birth control is a decision which should be made between the treating clinician and the patient
14. Known history of uncontrolled depression or any other psychiatric disease likely to be exacerbated by study treatment. A formal psychiatric assessment at baseline is not required.
15. Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study.)
16. Previous adverse reaction to the trial drug/s

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
patients are enrolled centrally
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
non randomised trial
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 8244 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 8245 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [3] 8246 0
Box Hill Hospital - Box Hill
Recruitment hospital [4] 8247 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [5] 8248 0
Concord Repatriation Hospital - Concord
Recruitment hospital [6] 8249 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [7] 8250 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [8] 8251 0
Nambour General Hospital - Nambour
Recruitment hospital [9] 8252 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [10] 8253 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [11] 8254 0
Royal Hobart Hospital - Hobart
Recruitment hospital [12] 8255 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 16304 0
3084 - Heidelberg
Recruitment postcode(s) [2] 16305 0
3220 - Geelong
Recruitment postcode(s) [3] 16306 0
3128 - Box Hill
Recruitment postcode(s) [4] 16307 0
2298 - Waratah
Recruitment postcode(s) [5] 16308 0
2139 - Concord
Recruitment postcode(s) [6] 16309 0
5042 - Bedford Park
Recruitment postcode(s) [7] 16310 0
3168 - Clayton
Recruitment postcode(s) [8] 16311 0
4560 - Nambour
Recruitment postcode(s) [9] 16312 0
4102 - Woolloongabba
Recruitment postcode(s) [10] 16313 0
5000 - Adelaide
Recruitment postcode(s) [11] 16314 0
7000 - Hobart
Recruitment postcode(s) [12] 16315 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 285788 0
Other Collaborative groups
Name [1] 285788 0
Australasian Leukaemia and Lymphoma Group
Address [1] 285788 0
Level 6, 372 Albert St
East Melbourne, Victoria, 3002
Country [1] 285788 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Level 6, 372 Albert St
East Melbourne, Victoria, 3002
Country
Australia
Secondary sponsor category [1] 284611 0
None
Name [1] 284611 0
Address [1] 284611 0
Country [1] 284611 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287796 0
Austin Health
Ethics committee address [1] 287796 0
145 Studley Road, Heidelberg, VIC 3084
Ethics committee country [1] 287796 0
Australia
Date submitted for ethics approval [1] 287796 0
01/04/2012
Approval date [1] 287796 0
14/01/2014
Ethics approval number [1] 287796 0

Summary
Brief summary
This study aims to determine the safety and efficacy of treatment with a tyrosine kinase inhibitor (TKI) and pegylated interferon in patients with previously untreated chronic myeloid leukaemia (CML).

Who is it for?
You may be eligible to join this study if you are aged at least 18 years and have been diagnosed with CML. You must have received no previous treatment for CML.

Trial details
All participants in this trial will commence treatment with the TKI oral nilotinib alone for 3 months. Provided the drug is tolerated, participants will commence injections of pegylated interferon at a dose of 30 micrograms per week. After a month of pegylated interferon and nilotinib treatment, and provided the pegylated interferon is tolerated, patients will escalate pegylated interferon treatment to a dose of 50 micrograms per week in combination with nilotinib. Participants will be assessed at regular timepoints until the end of the trial to determine the safety and clinical benefit of the treatments.
Treatment duration will be a minimum of 24 months.

This Phase II study will:

Investigate the survival benefit, the rate of remission and safety of the patients allocated to each group and compare the groups to eachother.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34531 0
Prof Timothy Hughes
Address 34531 0
Heamatology Department, SA Pathology, RAH Campus, Adelaide, SA 5000
Country 34531 0
Australia
Phone 34531 0
+61882223330
Fax 34531 0
Email 34531 0
timothy.hughes@health.sa.gov.au
Contact person for public queries
Name 17778 0
Ms Delaine Smith
Address 17778 0
Ground Floor, 35 Elizabeth Street, Richmond, VIC 3121
Country 17778 0
Australia
Phone 17778 0
+61 3 8373 9701
Fax 17778 0
Email 17778 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 8706 0
Prof Timothy Hughes
Address 8706 0
SA Pathology (RAH Campus)
Adealide SA, 5000
Country 8706 0
Australia
Phone 8706 0
+61 8 8222 3330
Fax 8706 0
Email 8706 0
timothy.hughes@health.sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We do not release individual participant data; all results are released as aggregate trial data.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary