Acute Myeloid Leukemia, Cellular Therapy, Cord Blood Stem Cell Transplantation, Stem Cell Transplantation, Stem Cell Transplantation, Hematopoietic
Conditions
Keywords
Grace, granulocyte-augmented cord blood transplantation, poor risk acute myeloid leukaemia, Cord Blood Transplantation, Myelodysplastic Syndrome, TP53, MECOM
Brief summary
Allogeneic stem cell transplantation is the only potentially curative therapy for patients with high-risk Acute Myeloid Leukaemia, but relapse is common and remains the leading cause of death. Patients with certain mutations and those transplanted without first clearing their disease have very poor outcomes with most relapsing soon after transplant, and then surviving only a few months. A recent trial at the Royal Manchester Children's Hospital used cord blood stem cells alongside a type of white blood cell called 'granulocytes' and produced surprisingly good outcomes for children with very resistant leukaemia. GRACE is a clinical trial for adults (\<55 years) with Acute Myeloid Leukaemia that has not responded to chemotherapy or harbours mutations that predict a very poor response to conventional transplant. Participants will receive a transplant using umbilical cord blood and be given additional infusions of white blood cells, called granulocytes. The trial will be split into two parts:-The first will study the safety of this new approach. The experience of the investigators in children is that granulocyte infusions cause a fever, rash and expansion of another type of white blood cell called lymphocytes. Children that did not have this reaction did not respond to treatment. The investigators therefore believe that the reaction is necessary for the treatment to work, but the investigators must ensure that it is safe in adult patients. The trial design allows the investigators to determine the dose of granulocytes that is best tolerated and most likely to be effective. The aim of the second part is to demonstrate that the new treatment is more effective than conventional transplantation. The study will be conducted in three NHS transplant centres. Patients will be recruited over 36 months and followed up for a minimum of 1 year. The study is funded by Blood Cancer UK.
Interventions
BIOLOGICALCord blood transplantation + conditioning + granulocytes of variable days according to study design
All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to all participants- but for a variable number of days starting on the day of transplant according to study design (1,3,5 or 7 days). The study consists of two phases- Phase 1 has two components (dose escalation and dose optimisation) to identify the Recommended Phase II Dose (RP2D) of granulocytes. Phase 2 will assess preliminary efficacy based Relapse Free Survival at 1 year.
Sponsors
University of Manchester
King's College Hospital NHS Trust
Institute of Cancer Research, United Kingdom
The Christie NHS Foundation Trust
Royal Marsden NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This trial utilises an innovative early phase seamless design, integrating dose-escalation and randomised dose-optimisation which is built on latest FDA and MDICT guidance. Phase I (up to 30 patients) will include two components: dose-escalation and dose-optimisation to identify the Recommended Phase II Dose (RP2D). In the dose-escalation component, a modified 2-stage Bayesian Time-to-event Continual Reassessment Method (TITE-CRM) will be used to determine the maximum tolerated dose and tolerable doses among 4 dose schedules. In the dose optimisation, subsequent patients will be randomised to selected tolerable doses to determine final RP2D based on tolerability, activity and other key secondary endpoints in consultation with the integrated TSC/DMC. Phase II will assess preliminary efficacy at the RP2D, based on relapse free survival at 1 year using a single-stage Bayesian design.
Eligibility
Sex/Gender
ALL
Age
16 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Availability of a suitable cord blood unit 2. Age between 16 and 55 years 3. Primary diagnosis of Acute Myeloid Leukaemia (AML) or MDS/AML (as defined by ICC 2022) fitting one or more of the following criteria: * TP53 mutation (single- or multi-hit) * Presence of inv(3) (q21.3q26.2) or t(3;3)(q21.3;q26.2) * Adverse risk (as per ICC 2022) and \>0.1% MRD by flow cytometry after 2 cycles of induction * AML (any risk) with partial remission (\<10% blasts) after 2 cycles induction * Early relapse (\<6 months) after chemotherapy alone (excluding t(16;16), inv(16) or t(8;21)) 4. Bone marrow performed within 28 days of starting conditioning chemotherapy demonstrates either: * \<10% blasts * \>10% blasts with a hypocellular background (must be discussed with the trial team) 5. Suitable fitness and organ function as per the following criteria: * Glomerular filtration rate \>50 mL/min/1.73m2 * Ejection fraction \>50% * FEV1 \>65% without dyspnoea on mild activity * AST/ALT \<3 x ULN * Bilirubin \<1.5 x ULN (excluding Gilbert's syndrome) * Performance Status (ECOG) of 0 or 1 6. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must agree to use appropriate, highly effective, contraception from the point of commencing therapy until 12 months after transplant
Exclusion criteria
1. AML Secondary to a myeloproliferative neoplasm 2. Active CNS disease 3. Prior allogeneic stem cell transplant 4. Participation in another clinical trial that would alter any aspect of the transplant protocol or that aims to reduce the subsequent risk of relapse (discuss with trial team if unsure) 5. History of cardiac arrhythmia 6. Ischaemic heart disease, valvular heart disease or congestive cardiac failure 7. Transient ischaemic attack or cerebrovascular accident 8. Rheumatologic disease (SLE, RA, polymyositis, mixed CTD or polymyalgia rheumatica) 9. Ulcerative colitis or Crohn's disease 10. Liver cirrhosis 11. Presence of an active second malignancy 12. Uncontrolled infection, including viral reactivation (CMV, EBV) 13. HIV positive 14. Hepatitis B/C active infection with measurable viral load (patients with chronic hepatitis B or C infection require clear documentation of absence of cirrhosis by either fibroscan or biopsy, regardless of viral load) 15. Pregnancy, breastfeeding, unwilling to use contraception 16. Contraindications to administration of pooled granulocytes 17. Previous history of sensitivity to granulocytes 18. Inability of patient to give informed consent 19. Any other organ dysfunction or co-morbidity that precludes transplant in the opinion of the investigator 20. Any concern by PI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency and Severity of Cytokine Release Syndrome (CRS) | Day 0 (day of allograft) to Day 28 post allograft | Frequency and Severity of Cytokine Release Syndrome (CRS) assessed via ASTCT Consensus Grading for CRS |
| Frequency and Severity of Acute Graft vs Host Disease | Day 0 (day of allograft) to Day 100 post allograft | Frequency and Severity of Acute Graft vs Host Disease assessed by modified Glucksberg criteria (revised by MAGIC) |
| Frequency and Severity of Chronic Graft vs Host Disease | Day 100 post allograft to Day 360 post allograft | Frequency and Severity of Chronic Graft vs Host Disease assessed by NIH criteria |
| Frequency of Transplant Related Mortality (TRM) | Day 0 (day of allograft) to Day 100 post allograft | Frequency of Transplant Related Mortality (TRM) defined as death due to any transplantation-related cause other than disease relapse |
| Frequency of Primary Graft Failure | Day 0 (day of allograft) to Day 28 post allograft | Frequency of Primary Graft Failure |
| Rate of Relapse-Free Survival (RFS) | Day 0 (day of allograft) to Day 360 post allograft | Relapse-free survival (RFS) rate: number of patients who remain relapse-free and alive within 1 year from transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Non-Relapse Mortality (NRM) | Day 0 (day of allograft) to Day 360 post allograft | Non-relapse mortality (NRM): number of patients who die from aetiology not related to disease relapse. |
| Duration of Overall Survival | Day 0 (day of allograft) to Day 360 post allograft | Overall survival: time from Day 0 to date of death from any cause. Patients who are alive will be censored at the date of last follow-up. |
| Duration of GvHD Free Relapse Free Survival (GRFS) | Day 0 (day of allograft) to Day 360 post allograft | GvHD-free, relapse-free survival (GRFS): time from day to the first occurrence of any of the following events: acute grade III-IV and/or chronic GvHD requiring systemic immune suppressive treatment, disease relapse or progression, or death from any cause. Patients who are alive and free of any of these event will be censored at the date of last follow-up. |
Countries
United Kingdom
Contacts
CONTACTJohnna Ward GRACE Trial Manager
PRINCIPAL_INVESTIGATORMark Williams, BA MB BChir PhD MRCP FRCPath
University of Manchester
PRINCIPAL_INVESTIGATORMili N Shah, BSc MBBS MRCP FRCPath
Kings College Hospital NHS Trust
Outcome results
None listed