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Trial registered on ANZCTR


Registration number
ACTRN12612000847819
Ethics application status
Not yet submitted
Date submitted
2/08/2012
Date registered
13/08/2012
Date last updated
19/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II study of midostaurin in combination with standard chemotherapy in newly diagnosed patients with Core Binding Factor Acute Myeloid Leukaemia
Scientific title
A Phase II study of failure-free survival following treatment with midostaurin in combination with standard chemotherapy in newly diagnosed patients with Core Binding Factor Acute Myeloid Leukaemia
Secondary ID [1] 280956 0
AMLM19
Universal Trial Number (UTN)
U1111-1126-2797
Trial acronym
AMLM19
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Core binding factor (CBF) Acute myeloid leukaemia (AML) 287072 0
Condition category
Condition code
Cancer 287386 287386 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive stages of treatment outlined in sections 1,2 and 3 sequentially.
1. 1 28 day cycle of induction chemotherapy consisting of idarubicin (IV 12mg/m^2 days 1-3), cytarabine(IV 100mg/m^2 days 1-7) and with twice daily oral 50mg midostaurin on days 8-21 of each cycle. Patients who do not achieve complete remission can undergo another cycle of induction therapy
2. Up to 4x28 day cycles, depending on tolerability, of high dose cytarabine (Ara-C) (3g/m^2 IV every 12 hours on days 1,3,5) with twice daily oral 50mg midostaurin on days 8-21 of each cycle. Consolidation chemotherapy should begin once patient has attained complete remission, including neutrophils of at least 1.0 x 10^9/L and platelets of at least 100 x 10^9/L.
3. Maintenance chemotherapy consisting of twice daily oral 50mg midostaurin on days 1-28 of each 28 day cycle for 12 consecutive cycles. Maintenance therapy should be commenced after haematologic recovery between days 36 and 64 from the
commencement of the last consolidation cycle
Intervention code [1] 285404 0
Treatment: Drugs
Comparator / control treatment
no control treatment
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287662 0
To establish the failure-free survival rates of patients with newly diagnosed CBF AML treated with Midostaurin in combination with standard chemotherapy induction and high dose AraC (HiDAC) consolidation and as a novel maintenance therapy.
Timepoint [1] 287662 0
12 months after last patient completes midostaurin treatment
Primary outcome [2] 287720 0
To establish the leukaemia-free survival rates for patients who achieve complete remission (CR) with protocol treatment.
Timepoint [2] 287720 0
12 months after last patient completes midostaurin treatment
Secondary outcome [1] 298594 0
To estimate the percentage of patients achieving CR following induction chemotherapy with midostaurin, the percentage of patients remaining in CR following consolidation chemotherapy and also the percentage of patients remaining in CR following 12 months of maintenance therapy with midostaurin.
Timepoint [1] 298594 0
at end of induction chemotherapy
at end of consolidation therapy
at completion of midostaurin treatment
Secondary outcome [2] 298595 0
To estimate overall survival.
Timepoint [2] 298595 0
12 months after last patient completes midostaurin treatment
Secondary outcome [3] 298596 0
To determine the safety and tolerability of the protocol treatment by tabulation of adverse events graded by NCI CTC version 4.03. Adverse events for analysis will be determined as they occur.
Timepoint [3] 298596 0
28 days after last dose of midostaurin
Secondary outcome [4] 298597 0
To determine the incidence of c-KIT, FLT3 and other gene (eg RAS, Jak 2) mutations and investigate the prognostic impact of mutation status on response and survival outcomes in the setting of treatment with midostaurin.
Timepoint [4] 298597 0
12 months after last patient completes midostaurin treatment
Secondary outcome [5] 298598 0
To compare response and survival outcomes for the AML M19 patient cohort with a previous cohort of CBF AML patients treated on the ALLG AML M13 clinical trial with high-dose cytarabine (Ara-C) containing regimens exclusive of anthracyclines.
Timepoint [5] 298598 0
12 months after last patient completes midostaurin treatment
Secondary outcome [6] 298599 0
To determine the kinetics of molecular complete remission (CRm) as described by the percentages of patients achieving CRm following induction chemotherapy, each consolidation cycle and maintenance treatment; and also the duration of CRm. CRm is defined as the reappearance of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts using quantitative polymerase chain reaction (QPCR) on peripheral blood or bone marrow.
Timepoint [6] 298599 0
at end of induction chemotherapy
after each consolidation cycle
at end of maintenance treatment
Secondary outcome [7] 298600 0
To investigate the correlation of CRm status over the course of treatment with the risk of subsequent relapse. CRm is defined as the reappearance of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts using QPCR on peripheral blood or bone marrow.
Timepoint [7] 298600 0
12 months after last patient completes midostaurin treatment
Secondary outcome [8] 298601 0
To evaluate Heath-Related Quality of Life (HRQOL) at disease diagnosis, at attainment of CR prior to consolidation therapy, and throughout maintenance and the 12 months following the conclusion of maintenance therapy using the FACT-Leu questionnaire.
Timepoint [8] 298601 0
disease diagnosis
attainment of CR
at 0,3,6,9,12 months throughout maintenance
at 0,3,6,9,12 months during the 12 months after conclusion of therapy
Secondary outcome [9] 298602 0
To compare response and survival outcomes for the AML M19 patient cohort with CBF patients on the AML M18 registry of all patients with suspected AML.
Timepoint [9] 298602 0
12 months after last patient completes midostaurin treatment

Eligibility
Key inclusion criteria
1. Newly diagnosed patients with a morphologically confirmed diagnosis of AML with t(8;21); RUNX1-RUNX1T1 or AML with inv(16) or t(16;16); CBFB-MYH11 by World Health Organisation criteria which includes patients with <20% blasts in the presence of cytogenetic or molecular evidence of a CBF subtype
2. Confirmation of CBF subtype by cytogenetic finding (including Fluorescence in situ hybridization (FISH)) of t(8;21)(q22;q22) or inv(16)(p13;q22) or t(16;16)(p13;q22) (either alone or in combination with other cytogenetic abnormalities) OR polymerase chain reaction (PCR) evidence of a CBF fusion transcript (RUNX1-RUNX1T1 or CBF-MYH11).
3. Age between 15 and 65 inclusive
4. Life expectancy at least 3 months
5. Females of childbearing potential use a highly effective method of contraception and a form of barrier contraception for the duration of the study and for 3 months after midostaurin treatment is ceased
6. Adequate renal and hepatic functions to enable safe delivery of chemotherapy.
a.Total bilirubin <1.5 x Upper Limit of Normal (ULN)
b.aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2.5 ULN
c.serum creatinine <250micromol/L
Patients not meeting these criteria should be discussed with Principal Investigator
7. An Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less
8. Patients must be registered prior to the commencement of induction therapy. Where there is a need for urgent commencement of induction therapy, patients with subsequent confirmation of the CBF subtype following commencement of induction therapy may be considered, after discussion with a study Principal Investigator, for inclusion in this trial. The continuation, or modification, of the induction phases of their treatment will be determined by the investigator in consultation with a Principal Investigator, but post-remission consolidation therapy will follow the treatment plan for this study (AMLM19).

9. Has provided written informed consent
Minimum age
15 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior therapy for AML (Hydroxyurea allowed up to 5 days and circumstances in Inclusion criterion 8 will be considered)
2. Patients with central nervous sytem (CNS) involvement with AML
3. Serious cardiac or pulmonary dysfunction precluding the delivery of the proposed therapy
4. Women who are pregnant or lactating. Women of child-bearing potential must have a negative serum pregnancy test at Screening.
5. Prior diagnosis of cancer that was:
a.more than 5 years prior to current diagnosis with subsequent evidence of disease recurrence or clinical expectation of recurrence is greater than 10%
b.within 5 years of current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma or carcinoma in situ of the cervix
6. Contraindication to the use of study drugs

7. Severe active infection
8. Known human immunodeficiency virus (HIV) or Hepatitis C Virus (HCV) infection or Hepatitis V virus surface antigen (HBV-sAg) positivity

9. Has any other clinically important abnormalities as determined by the investigator that may interfere with his or her participation in or compliance with the study
10. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

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. there is no blinding in this study
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
no randomisation in study
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
Withdrawn
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
1/03/2013
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment outside Australia
Country [1] 3997 0
New Zealand
State/province [1] 3997 0

Funding & Sponsors
Funding source category [1] 285749 0
Other Collaborative groups
Name [1] 285749 0
Australasian Leukaemia and Lymphoma Group
Country [1] 285749 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] 284575 0
None
Name [1] 284575 0
nil
Address [1] 284575 0
Country [1] 284575 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 287756 0
Ethics committee address [1] 287756 0
Ethics committee country [1] 287756 0
Date submitted for ethics approval [1] 287756 0
01/01/2013
Approval date [1] 287756 0
Ethics approval number [1] 287756 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33507 0
A/Prof Paula Marlton
Address 33507 0
Department of Haematology Princess Alexandra Hospital 199 Ipswich Road Woollongabba Brisbane Qld 4102 Australia
Country 33507 0
Australia
Phone 33507 0
+61 7 3176 2390
Fax 33507 0
Email 33507 0
Paula_Marlton@health.qld.gov.au
Contact person for public queries
Name 16754 0
Delaine Smith
Address 16754 0
Level 6, 372 Albert St
East Melbourne, Victoria
Australia. 3002
Country 16754 0
Australia
Phone 16754 0
+61 3 9656 2760
Fax 16754 0
Email 16754 0
delaine.smith@petermac.org
Contact person for scientific queries
Name 7682 0
Paula Marlton
Address 7682 0
Department of Haematology
Princess Alexandra Hospital
199 Ipswich Road
Woollongabba Brisbane Qld 4102 Australia
Country 7682 0
Australia
Phone 7682 0
+61 7 3176 2390
Fax 7682 0
Email 7682 0
Paula_Marlton@health.qld.gov.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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