Efficacy of assigning treatment for participants with Chronic Myelomonocytic Leukaemia based on their individual molecular results (lenzilumab plus azacitidine versus sodium ascorbate plus azacitidine). PREACH-M: PREcision Approach to CHronic Myelomonocytic Leukaemia.

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 a .... 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. Read more

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 .... 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 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.Note: the Adjusted Body Weight formula should be used for participants with a BMI of = 30. Actual Body weight should be used when BMI is < 30. 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. Read more

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 sur .... 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). Read more

Can healthy volunteers participate?

No