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Trial registered on ANZCTR


Registration number
ACTRN12621000223831p
Ethics application status
Submitted, not yet approved
Date submitted
6/01/2021
Date registered
3/03/2021
Date last updated
3/03/2021
Date data sharing statement initially provided
3/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of assigning treatment for participants with Chronic Myelomonocytic Leukaemia based on their individual molecular results (lenzilumab plus azacitidine versus sodium ascorbate plus azacitidine).
Scientific title
Precision Medicine for Chronic Myelomonocytic Leukaemia in Adults: A phase II Trial Studying the Efficacy of Lenzilumab and High Dose Ascorbate with Azacitidine Based on Molecular Profiling.
Secondary ID [1] 302798 0
Nil known
Universal Trial Number (UTN)
U1111-1261-2350
Trial acronym
PREACH-M

(PREACH-M: PREcision Approach to CHronic Myelomonocytic Leukaemia)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Myelomonocytic Leukaemia 319759 0
Condition category
Condition code
Cancer 317694 317694 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This prospective study will assess whether treatment responses for participants with Chronic Myelomonocytic Leukaemia can be improved by targeting certain mutation sub-groups based on individual molecular profiling.

As part of the screening process, participants will be required to have a bone marrow aspirate and trephine. During this procedure, 9 mL of bone marrow aspirate will be collected for central mutation profiling which is a test used to detect certain acquired mutations that can be present in CMML. The most common genes affected in CMML include TET2 and a group of genes belonging to the RAS pathway (NRAS/KRAS/CBL). Both TET2 and RAS pathway genes contribute to CMML, but the way in which they work is different. As a result, we need to tailor our medications specifically to switch them off. Before participants are enrolled in this research study, we will need to assess whether either of these groups of genes have been affected in their case. If they are, the participant may be eligible for this study. Genetic testing is complex and it will take approximately 3 weeks for results to become available.

Participants with RAS pathway mutations in will receive lenzilumab in combination with azacitidine, while patients with TET2 mutations will receive sodium ascorbate plus azacitidine. Participants who are found to have both TET2 and RAS pathway mutations (NRAS/KRAS/CBL) will be allocated to the lenzilumab/azacitidine arm of the study. Participants who are negative for both TET2 and NRAS/KRAS/CBL mutations (Variant Allele Frequency [VAF] >= 3%) at screening will be considered screen failures.

Drug schedules:
Lenzilumab/Azacitidine Arm (total of 24 Cycles). Each Cycle is 28 days.
• Azacitidine (subcutaneous) 75 mg/m2 on days 1-5, 8-9 or days 1-7 (for a total of 7 doses per 28 day cycle, at the local institution’s discretion according to the institution's standard Azacitidine protocols).
• Lenzilumab (intravenous) 552 mg on days 1 & 15 of Cycle 1. Day 1 only for all subsequent cycles.

High Dose Sodium Ascorbate/Azacitidine Arm (total of 24 Cycles). Each cycle is 28 days.
• Azacitidine (subcutaneous) 75 mg/m2 on days 1-5, 8-9 or days 1-7 (for a total of 7 doses per 28 day cycle, at the local institution’s discretion according to their standard azacitidine protocol).
• Sodium Ascorbate (intravenous) 30 grams on days 1-5, 8-9 or days 1-7 (15 grams for 1st dose only, 30 grams thereafter if no evidence of tumour lysis syndrome). This will be administered on the same days as the azacitidine, according to the institution's standard protocol for azacitidine administration.
• Sodium Ascorbate (oral) 1.1 grams on days where intravenous Sodium Ascorbate is not scheduled. Oral dosing will be self-administered at home.

During the active treatment phase of the study, participants will be required to attend clinic visits with their doctor on days 1 & 15 of the first cycle, and then on day 1 of each subsequent 28-day cycle to assess how the participant is tolerating the therapy and ensure ongoing safety. In addition to regular safety blood tests throughout each cycle, participants will have disease response assessments scheduled after 3, 6, 12 and 24 cycles of therapy to measure their disease response. Such assessments include blood tests, bone marrow aspirate and trephine, ultrasound of the spleen, physical exam and assessment of transfusion requirements and clinical symptoms.

Participants who complete 24 cycles of active treatment will then enter the follow-up phase of the study where they will be followed up every 6 months for 24 months for survival, disease status and further CMML-related treatment. For patients with confirmed progressive disease or relapse during the active treatment phase of the study, further study treatment should cease. They will remain on study and be followed up for disease status, survival and further CMML-related treatment every 6 months until 48 months from Cycle 1, Day 1. During the follow-up period, participants will no longer receive any investigational drugs but are permitted to receive any CMML treatment at the discretion of the treating clinician (including azacitidine who are able to access it).

No visits or tests are required as part of the follow-up phase. Participants who continue to receive treatment/care at the study institution and who allow the study team to access their progress notes may not receive any follow-up phone calls. Participants who receive ongoing care at a different institution, and who consent to ongoing follow-up, will have their doctor or study coordinator contact them via a telephone call every six months. This call will take approximately 15 minutes in total.
Intervention code [1] 319079 0
Treatment: Drugs
Comparator / control treatment
Results from each cohort will be compared to historical trials utilizing azacitidine alone and the South Australian MDS Registry data from.1st January 2012 until 1st May 2026.
Control group
Historical

Outcomes
Primary outcome [1] 325737 0
To assess the frequency of complete response (CR) and partial response (PR) at any point during the first 12 months of active therapy according to Savona Criteria.

(composite outcome)
Timepoint [1] 325737 0
Any point during the first 12 months
Secondary outcome [1] 388933 0
Overall survival (as measured by medical records/follow-up.)
Timepoint [1] 388933 0
2 years from Cycle 1, Day 1
Secondary outcome [2] 388934 0
Progression-free survival (as measured by medical records/follow-up)
Timepoint [2] 388934 0
2 years from cycle 1, day 1
Secondary outcome [3] 388935 0
The proportion of participants who derive a clinical benefit according to Savona Criteria
Timepoint [3] 388935 0
The proportion of participants who derive a clinical benefit at any point during the 24 months of active therapy. This will be evaluated at the conclusion of study.
Secondary outcome [4] 388936 0
Assessment of the impact of treatment on physical capacity by serial assessment of Multidimensional Geriatric Assessment.
Timepoint [4] 388936 0
At baseline, Cycles 3, 6. 9, 12, 18, 24 and Early withdrawal.
Secondary outcome [5] 388937 0
Toxicity evaluation, both haematological and non-haematologic for both arms of the study by assessment of adverse event reporting and test results.

(Composite outcome)

Tests include blood tests and bone marrow tests. Toxicity will also be evaluated by asking participants about their health at every visit.
Timepoint [5] 388937 0
Throughout the 24 months of active therapy. (Assessed throughout as serious adverse events reported immediately). Participants will be asked about their health at every visit (baseline, cycle 1 days 1, 2, 4, 7, 15 & 22 and then day 1 of each cycle (maximum of 24 cycles). Blood tests will be collected every visit (baseline, cycle 1 days 1, 2, 4, 7, 15 & 22 and then day 1 of each cycle (maximum of 24 cycles). Bone marrow tests will be collected after 3, 6, 12 & 24 cycles of treatment.
Secondary outcome [6] 391192 0
Assessment of the impact of treatment on functional capacity by serial assessment of Multidimensional Geriatric Assessment.
Timepoint [6] 391192 0
At baseline, Cycles 3, 6. 9, 12, 18, 24 and Early withdrawal.
Secondary outcome [7] 391193 0
Assessment of the impact of treatment on social wellbeing by serial assessment of quality of life questionnaires.
Timepoint [7] 391193 0
At baseline, Cycles 3, 6. 9, 12, 18, 24 and Early withdrawal.

Eligibility
Key inclusion criteria
1. Confirmed diagnosis of CMML, including t-CMML, satisfying the WHO 2016 criteria
2. Aged 18 or older
3. Cytopenia, constitutional symptoms or proliferative CMML (white blood cell count >=13
x10^9/L)
4. Detection of TET2 mutation or NRAS/KRAS/CBL mutation at a variant allele frequency
of >=3%. Participants who are found to have both TET2 and RAS pathway mutations will
be allocated to the lenzilumab/azacitidine arm of the study.
5. Eastern Cooperative Oncology Group (ECOG) performance status of <=2.
6. Based on known non-CMML related medical history, expected to have a life
expectancy of >= 24 months.
7. Must have the following local laboratory results:
a. Liver function (total bilirubin <=1.5* x upper limit of normal [ULN], aspartate
aminotransferase [AST] and/or alanine aminotransferase [ALT] <=3 x ULN). For
participants with hepatomegaly due to extramedullary haematopoiesis, AST
and/or ALT must be < 5 x ULN. *For participants with total bilirubin >1.5 x ULN,
direct bilirubin must be <= ULN.
b. Kidney function: creatinine clearance >30 mL/min using Cockcroft-Gault formula.
8. Ability to understand the requirements of the study and informed consent.
9. Reproductive status
a. Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
hours prior to the start of study drug
b. Women must not be breastfeeding
c. WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drug, plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion
d. Men who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug plus 90
days (duration of sperm turnover) for a total of 90 days post-treatment
completion.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior hypomethylating or intensive cytotoxic treatment for CMML except for
hydroxyurea. Hydroxyurea may be given prior to starting active protocol treatment
and during the first 14 days of Cycle 1 only
2. Prior treatment with an investigational agent, or radiotherapy within 28 days before
Cycle 1 Day 1 (or within 5 half-lives of the investigational agent, whichever is longer).
Participants must have recovered from the toxic effects of that therapy to <= Grade 1 or
baseline grade.
3. Major surgery within 2 weeks or having not recovered from surgery.
4. Treatment with G-CSF within 7 days of screening or GM-CSF within 28 days of
screening.
5. Serious medical or psychiatric illness likely to interfere with participation in this clinical
study
6. Other concurrent uncontrolled medical conditions. These include, but are not limited
to: uncontrolled diabetes, uncontrolled infections, acute or chronic liver and renal
disease, uncontrolled cardiovascular conditions, including ongoing cardiac arrhythmias
(e.g. ventricular arrhythmias or Torsades de Pointes, or third-degree heart block without
pace maker insertion) or uncontrolled congestive cardiac failure.
7. Myocardial infarction or clinically significant pericardial effusion within the past month.
8. Another primary malignant disease that requires active treatment. Basal or squamous cell skin carcinomas adequately treated are allowed.
9. Acute or chronic liver disease (including chronic hepatitis B and C infections). Hepatitis B Virus core antibody positivity is not an automatic exclusion.
10. Patients with known active Hepatitis A infection. Testing for Hepatitis A is not required as part of screening for this study.
11. Participants with known human immunodeficiency viruses (HIV). Screening for HIV is not required for this study.
12. Participants who are unable to comply with requirements for contraception as per study requirements.
13. Prior allogeneic stem cell transplantation.
14. Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study).

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)
NA
Masking / blinding
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Not yet 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)
QLD,SA,WA
Recruitment hospital [1] 18029 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 18030 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 18032 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 32005 0
5000 - Adelaide
Recruitment postcode(s) [2] 32006 0
4029 - Herston
Recruitment postcode(s) [3] 32008 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 307225 0
Government body
Name [1] 307225 0
Medical Research Future Fund Grant, National Health and Medical Research Council.
Address [1] 307225 0
NHMRC:
Research Administration Section
National Health and Medical Research Council
GPO Box 1421
Canberra City ACT 2601
Country [1] 307225 0
Australia
Primary sponsor type
Other
Name
South Australian Health & Medical Research Institute Ltd
Address
PO Box 11060, Adelaide SA 5001
Country
Australia
Secondary sponsor category [1] 307831 0
None
Name [1] 307831 0
Address [1] 307831 0
Country [1] 307831 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307321 0
CENTRAL ADELAIDE LOCAL HEALTH NETWORK HUMAN RESEARCH ETHICS COMMITTEE
Ethics committee address [1] 307321 0
Level 3, Roma Mitchell House
136 North Terrace, Adelaide SA 5000
Ethics committee country [1] 307321 0
Australia
Date submitted for ethics approval [1] 307321 0
01/02/2021
Approval date [1] 307321 0
Ethics approval number [1] 307321 0

Summary
Brief summary
This study is investigating the efficacy of assigning targeted therapy to Chronic Myelomonocytic Leukaemia (CMML) patients based on their individual molecular profile.

Who is it for?
You may be eligible if you are aged 18 years or over with a confirmed diagnosis of CMML with detection of TET2 and/or RAS pathway mutations during the genetic testing component of this study.

Study details
Participants will be assigned to each arm based on their individual molecular results:
Arm 1: lenzilumab plus azacitidine (for participants with RAS-pathway mutations, or participants harbouring both TET2+RAS Pathway mutations)
Arm 2: ascorbate plus azacitidine (for participants with TET2-only mutations)
Each arm involves 24 cycles of treatment. Each cycle is 28 days. Participants who complete 24 cycles of active treatment will then enter the follow-up phase of the study where they will be followed up every 6 months for 24 months for survival, disease status and further CMML-related treatment. For participants who have confirmed progressive disease or relapse during the active treatment phase of the study, further treatment will cease. They will remain on study and be followed up for survival, disease status, and further CMML-related therapy every 6 months until 48 months from Cycle 1, Day 1.

The results of this clinical trial will inform a rational targeted therapy management approach for a rare disease and will potentially be used to update clinical guidelines and inform healthcare providers.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106822 0
Dr Devendra Hiwase
Address 106822 0
Haematology Clinical Trials
Royal Adelaide Hospital
Port Road
Adelaide SA 5000
Country 106822 0
Australia
Phone 106822 0
+61 8 7074 2709
Fax 106822 0
+61 8 8429 6099
Email 106822 0
Devendra.Hiwase@sa.gov.au
Contact person for public queries
Name 106823 0
Mrs Lisa Carne
Address 106823 0
South Australian Health and Medical Research Institute
PO Box 11060
Adelaide, South Australia 5001
Country 106823 0
Australia
Phone 106823 0
+61 8 8128 4415
Fax 106823 0
Email 106823 0
Lisa.Carne@sahmri.com
Contact person for scientific queries
Name 106824 0
A/Prof Daniel Thomas
Address 106824 0
South Australian Health and Medical Research Institute
PO Box 11060
Adelaide, South Australia 5001
Country 106824 0
Australia
Phone 106824 0
+61 8 8128 4317
Fax 106824 0
Email 106824 0
daniel.thomas@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report (de-identified).
What supporting documents are/will be available?
No other documents available
Summary results
No Results