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Trial registered on ANZCTR


Registration number
ACTRN12617000084381
Ethics application status
Approved
Date submitted
7/01/2017
Date registered
16/01/2017
Date last updated
1/06/2020
Date data sharing statement initially provided
11/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
BLAM- A phase IIb study of Blinatumomab + Cytarabine (AraC) and Methotrexate in adult B-precursor Acute Lymphoblastic Leukaemia
Scientific title
BLAM- A phase IIb study of Blinatumomab + Cytarabine (AraC) and Methotrexate in adult B-precursor Acute Lymphoblastic Leukaemia
Secondary ID [1] 290859 0
ALLG ALL8
Universal Trial Number (UTN)
Trial acronym
BLAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
newly diagnosed acute lymphoblastic leukaemia 301547 0
Condition category
Condition code
Cancer 301266 301266 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Prephase 15 day debulking therapy consisting of 10mg/m^2/day vincristine days 1-4 and days 11-14 IV or oral (at the discretion of treating oncologist), 2mg/day IV vincristine day 1 and day 11, cyclohosphamide 150mg.m^2 twice daily IV day 1 to day 3.
A cycle: Blinatumomab 28 micrograms per day continuous iv infusion for alternative 28 day cycles
B cycle: Methylprednisolone 50mg/day twice daily oral day 1 to day 3, methotrexate 200mg/m^2 IV 2 hour continuous infusion on day 1, methotrexate 800mg/m^2 IV 22 hour continuous infusion on day 1, cytarabine 3000mg/m^2/ day IV twice daily on day 2 and day 3 in alternating 28 day cycles with A cycle treatment for a total of 4 cycles of A cycles and 4 cycles of B cycles.
Maintenance therapy will be vincristine 2mg IV day 1, prednisolone 200mg/day orally days 1-5, mercaptopurine 50mg/m^2 orally for 28 days three times a day, methotrexate 20mg/m^2 orally per week on days 1, 8, 15 and 21 repeated at 28 day intervals for 24 months.
Intervention code [1] 296803 0
Treatment: Drugs
Comparator / control treatment
single arm study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300675 0
Event free status. Events include death from any cause, refractory disease (failure to achieve complete response at the end of Blinatumomab cycle 2A), progressive disease, relapsed disease , off protocol for any reason (other than ASCT), or deemed lost to follow-up
Timepoint [1] 300675 0
2 years from date of registration
Secondary outcome [1] 330586 0
Event free survival which includes death from any cause, refractory disease, progressive disease, relapsed disease or off protocol for any reason (other than for Allogeneic stem cell transplant).
Timepoint [1] 330586 0
after last patient completes 2 years from registration
Secondary outcome [2] 330587 0
Clinical response defined as achievement of complete response
Complete response determined by:
Absence of circulating blasts or extramedullary disease
No reoccurrence for 4 weeks
Absolute Neutrophil Count (ANC) >1000/microL
Platelets >100,000/microL
Timepoint [2] 330587 0
at the end of the Blinatumomab cycle 2A.
Secondary outcome [3] 330588 0
overall survival
Timepoint [3] 330588 0
after last patient completes 5 years from trial registration
Secondary outcome [4] 330589 0
tolerability- determined by dose intensity and the number of patients completing per protocol therapy until the end of cycle 4B.
Timepoint [4] 330589 0
end of cycle 4B, end of 1st 6 cycles of maintenance therapy, end of maintenance therapy
Secondary outcome [5] 330590 0
Safety- adverse events
Assessed via biochemistry, vital signs, ECG
Timepoint [5] 330590 0
30 days after last dose of blinatumomab
Secondary outcome [6] 330591 0
cytokine release syndrome rates in induction
Timepoint [6] 330591 0
completion of cycle 1B therapy
Secondary outcome [7] 330592 0
Depth of response defined as achievement of minimal residual disease (MRD) negative state as assessed by quantitative real-time polymerase chain reaction assay.
Timepoint [7] 330592 0
at the ends of cycles 1B, 2B and 4B
Secondary outcome [8] 330593 0
quality of life using Fact Leu
Timepoint [8] 330593 0
at the end of cycles 1B, 2B and 4B.

Eligibility
Key inclusion criteria
1. Age 40 to 65 (inclusive)
2. Newly diagnosed B-precursor acute lymphoblastic leukaemia without Ph positive disease
3. CD19 positive diseases
4. Provision of informed consent for this study
5. Patient has a life-expectancy from non-leukaemia related causes ofgreater than 3 months
6. ECOG performance status of 0 to 2 inclusive
7. Absence of serious cardiac, pulmonary, hepatic or renal disease. A serum creatinine of less than 1.5 times the institutional upper limit of normal (ULN) and serum bilirubin less than 2.5 times ULN is required
8. Normal left ventricular ejection fraction, as per local institutional standards
9. No contraindication for use of study drugs
Minimum age
40 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. A history of major medication non-compliance
2. Evidence of known active central nervous system (CNS) leukaemia
3. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis, with the exception of history of CNS leukaemia that is controlled with intrathecal therapy
4. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
5. Pregnant or lactating
6. Women of child-bearing potential who are not willing to use 2 highly effective methods of contraception while receiving study therapy and for 3 months after completion
7. Men who are not willing to use 2 highly effective methods of contraception while receiving study therapy and for 3 months after completion
8. Men who have a pregnant partner and are not willing to use a condom while performing sexual activity or for 3 months after completion of study therapy
9. Subjects with a known sensitivity to immunoglobulins or other components of the investigational product
10. Previous diagnosis of cancer within 5 years of current diagnosis except successfully treated Basal Cell Carcinoma, Squamous Cell Carcinoma or carcinoma in situ of the cervix
11. HIV positive
12. Significant active liver disease or active Hepatitis C Virus (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B Virus (HBV; DNA PCR-positive) infection. Only patients who are HBV surface antigen (HBVsAg) and/or HBV core antibody (HBVcAb) positive are required to undergo HBV DNA PCR testing. Subjects with PCR-negative HBV or who are HBV core antibody positive are permitted in the study but must be on HBV prophylaxis.
13. Presence of New York Heart Association stage 2 or higher cardiac symptoms not related to the disease under study
14. Significant concomitant illnesses which would in the investigator’s opinion not make the patient a good candidate for the trial
15. Any other form of known condition or behaviour that deems the patient a poor candidate
16. Subjects who have been vaccinated with live virus vaccines less than 2 weeks prior to registration.

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)
allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
single arm 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)
Safety/efficacy
Statistical methods / analysis
trial is a proof of concept trial.An observed event-free rate of 63% at 2 years is deemed to be an important signal. The lower clinical threshold for futility will be set at 50% at 2 years.
Using the Neuenschwander Proof of Concept (PoC) approach the criteria for PoC will be set to;
An observed event-free rate at 2 years of =63%
Posterior probability that the true rate exceeds 50% is >90% (given observed data)

It could be described as the “Bayesian power” in this context and if the true rate is > 67%, a sample size of 60 is a justifiable upper limit on the sample size; with higher, true event-free rates the probability that both PoC criteria are met exceeds 80% at substantially smaller sample sizes. With a sample size of 30 there is a reasonable probability (>80%) of meeting the PoC criteria for the primary endpoint when the true event-free rate at 2 years is 70% or more. The probability that the PoC criteria will be met when the true rate is 50% or less, is 10% or less when more than 25 patients have been assessed.

Recruitment
Recruitment status
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)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 7239 0
The Alfred - Prahran
Recruitment hospital [2] 9763 0
Box Hill Hospital - Box Hill
Recruitment hospital [3] 9764 0
The Canberra Hospital - Garran
Recruitment hospital [4] 9765 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 9766 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [6] 9767 0
Royal Perth Hospital - Perth
Recruitment hospital [7] 9768 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [8] 9769 0
Westmead Hospital - Westmead
Recruitment hospital [9] 9770 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [10] 9771 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 18546 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 18544 0
2065 - St Leonards
Recruitment postcode(s) [3] 18547 0
2145 - Westmead
Recruitment postcode(s) [4] 18542 0
2605 - Garran
Recruitment postcode(s) [5] 18549 0
3000 - Melbourne
Recruitment postcode(s) [6] 15004 0
3004 - Prahran
Recruitment postcode(s) [7] 18541 0
3128 - Box Hill
Recruitment postcode(s) [8] 18548 0
4029 - Herston
Recruitment postcode(s) [9] 18543 0
5000 - Adelaide
Recruitment postcode(s) [10] 18545 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 295290 0
Other Collaborative groups
Name [1] 295290 0
Australasian Leukaemia and Lymphoma Group
Address [1] 295290 0
35 Elizabeth St, Richmond, VIC 3121
Country [1] 295290 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
35 Elizabeth St, Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 294112 0
None
Name [1] 294112 0
Address [1] 294112 0
Country [1] 294112 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296625 0
Alfred Hospital HREC
Ethics committee address [1] 296625 0
55 Commercial Road, Melbourne, VIC, 3004
Ethics committee country [1] 296625 0
Australia
Date submitted for ethics approval [1] 296625 0
13/11/2017
Approval date [1] 296625 0
22/12/2017
Ethics approval number [1] 296625 0
HREC/17/Alfred/200

Summary
Brief summary
The primary purpose of this trial is to evaluate the safety and efficacy of a Blinatumomab, Cytarabine (AraC) and Methotrexate therapy protocol for the treatment of acute lymphoblastic leukaemia.

Who is it for?
You may be eligible to enroll in this trial if you are aged 40 to 65 years, and have been newly diagnosed with B-precursor acute lymphoblastic leukaemia without Ph positive disease.

Study details
All participants enrolled in this trial will receive the same therapy protocol. This involves a 15-day debulking treatment with oral and/or intravenous vincristine followed by eight 28-day cycles alternating between intravenous blinatumomab therapy and intravenous methotrexate, methylprednisolone and cytarabine. After completing these alternating cycles, maintenance treatment will continue in 28-day cycles for 24 months with a combination of intravenous vincristine and oral prednisolone, mercaptopurine and methotrexate.

Participants will be asked to complete questionnaires regarding their quality of life and will undergo assessments for disease progression, side effects and survival for 5 years.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71530 0
Dr Shaun Fleming
Address 71530 0
The Alfred Hospital
55 Commercial Road, Prahran, VIC 3004
Country 71530 0
Australia
Phone 71530 0
+61 3 9076 2000
Fax 71530 0
Email 71530 0
S.Fleming2@alfred.org.au
Contact person for public queries
Name 71531 0
Ms Delaine Smith
Address 71531 0
Australasian Leukaemia and Lymphoma Group Ground floor, 35 Elizabeth St, Richmond, VIC 3121
Country 71531 0
Australia
Phone 71531 0
+61 3 8373 9701
Fax 71531 0
Email 71531 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 71532 0
Dr Shaun Fleming
Address 71532 0
The Alfred Hospital
55 Commercial Road, Prahran, VIC 3004
Country 71532 0
Australia
Phone 71532 0
+61 3 9076 2000
Fax 71532 0
Email 71532 0
S.Fleming2@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
No Results