GRanulocyte Augmented Cord Blood Transplantation for Poor Risk leukaEmia

Official title

A Multi-centre Phase I/II Trial of Granulocyte-augmented Cord Blood Transplantation for Young Adults With Very Poor Risk Acute Myeloid Leukaemia.

Overview

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

• Biological Cord 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 Do

Primary outcome measures

• Frequency and Severity of Cytokine Release Syndrome (CRS) [Time frame: Day 0 (day of allograft) to Day 28 post allograft]
• Frequency and Severity of Acute Graft vs Host Disease [Time frame: Day 0 (day of allograft) to Day 100 post allograft]
• Frequency and Severity of Chronic Graft vs Host Disease [Time frame: Day 100 post allograft to Day 360 post allograft]
• Frequency of Transplant Related Mortality (TRM) [Time frame: Day 0 (day of allograft) to Day 100 post allograft]
• Frequency of Primary Graft Failure [Time frame: Day 0 (day of allograft) to Day 28 post allograft]
• Rate of Relapse-Free Survival (RFS) [Time frame: Day 0 (day of allograft) to Day 360 post allograft]

Secondary outcome measures (3)

• Frequency of Non-Relapse Mortality (NRM) [Time frame: Day 0 (day of allograft) to Day 360 post allograft]
• Duration of Overall Survival [Time frame: Day 0 (day of allograft) to Day 360 post allograft]
• Duration of GvHD Free Relapse Free Survival (GRFS) [Time frame: Day 0 (day of allograft) to Day 360 post allograft]

Eligibility criteria

Inclusion criteria

• Availability of a suitable cord blood unit
• Age between 16 and 55 years
• 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))
• 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)
• 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
• 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

• AML Secondary to a myeloproliferative neoplasm
• Active CNS disease
• Prior allogeneic stem cell transplant
• 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)
• History of cardiac arrhythmia
• Ischaemic heart disease, valvular heart disease or congestive cardiac failure
• Transient ischaemic attack or cerebrovascular accident
• Rheumatologic disease (SLE, RA, polymyositis, mixed CTD or polymyalgia rheumatica)
• Ulcerative colitis or Crohn's disease
• Liver cirrhosis
• Presence of an active second malignancy
• Uncontrolled infection, including viral reactivation (CMV, EBV)
• HIV positive
• 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)
• Pregnancy, breastfeeding, unwilling to use contraception
• Contraindications to administration of pooled granulocytes
• Previous history of sensitivity to granulocytes
• Inability of patient to give informed consent
• Any other organ dysfunction or co-morbidity that precludes transplant in the opinion of the investigator
• Any concern by PI

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 3 centers

• Kings College Hospital NHS Trust — London
• The Royal Marsden Hospital NHS Foundation Trust — London
• The Christie NHS Foundation Trust — Manchester

Identifiers

NCT: NCT07372885 · 357519

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗