This study has been transitioned to CTIS with ID 2024-517583-36-01 check the CTIS register for the current data. Primary:1) Examine the safety (including assessment of rate of graft failure) and feasibility of infusing a single ECT-001-expanded cord…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and feasibility of infusing a single ECT-001-expanded blood cord
Evaluate relapse-free survival at 1- and 2-years post-transplant.
Relapse free and overall survival (RFS and OS) will be monitored throughout the
study and in particular at 1, and 2 years post-transplant.
RFS and OS will be measured from the time of transplant until progression,
death or last follow-up.
RFS: an event is defined as relapse/progression or death.
OS: an event is defined as death.
Secondary outcome
Kinetics of hematopoietic engraftment
- Neutrophil engraftment
- Platelet engraftment
Treatment related mortality (TRM)
Incidence of acute and chronic GVHD
Severe infectious complications
Pre-engraftment/engraftment syndrome requiring therapy
Exploratory endpoint: Quality of life
Background summary
Umbilical cord blood (CB) is an effective and widely used source of stem cells
for patients undergoing hematopoietic stem cell transplantation. Importantly,
CB offers some distinct advantages over conventional stem cell sources. Because
CB is collected at the time of birth and then cryopreserved until matched to a
specific recipient, CB donors are readily available with no donor attrition.
Furthermore, there is greater tolerance for human leukocyte antigen (HLA)
mismatching without an increase in graft versus host disease (GVHD) thereby
increasing the donor pool, especially for minority or mixed ethnicity patients.
However, CB grafts contain approximately 1/10th the number of hematopoietic
stem cells relative to conventional bone marrow or peripheral blood stem cell
graft, resulting in a known increased risk of delayed engraftment or graft
failure and early post-transplant related morbidity and mortality. Thus, the
low cell dose in a CB graft remains a significant barrier to the more
widespread use of this stem cell source.
One of the first strategies aimed at increasing the available cell dose for CB
transplant (CBT) was the use of two CB donors for transplant, a *double* CBT.
This approach was found to be safe, resulted in a reduced incidence of primary
graft failure, and significantly advanced the CBT field making this a standard
approach for adult patients. However, even with a double unit CB graft whereby
the cell dose is doubled, there is still a significant delay in hematopoietic
recovery. Infused CD34+ cell dose is felt to be the most important predictor of
the kinetics of myeloid engraftment. Furthermore, CBT patients are at a higher
risk of early non-relapse mortality (NRM), particularly in those patients with
a time to neutrophil engraftment of >=26 days. Moreover, an ANC of >100 on any
given day post stem cell transplant has been shown to be a critical threshold
for a decreased risk of mortality before day 100 post-transplant. Thus, the
significant delay in myeloid recovery that is observed in CBT recipients
remains a critical barrier to successful outcomes in the CBT setting.
Strategies aimed at shortening the time to neutrophil and platelet recovery
after CBT are important for effective reduction of the high risk of non-relapse
mortality that is experienced by CBT recipients and for improving overall
survival (OS) and is an area of great unmet medical need.
Excellthera-001-CB (ECT-001-CB) is a technology enabling expansion of CB units
that is based on the use of a small molecule, UM171, and an optimized culture
system.
UM171 was identified and reported to actively promote HSC expansion while
preventing the differentiation of CD34+CD45RA- cells. The application of UM171
to CB expansion has proven to be successful in mice, since the infusion of cord
blood expanded with UM171 in the fed-batch system into NSG mice demonstrated
their ability to induce long-term (up to 30 weeks) human multilineage
engraftment, their self-renewal capability through secondary transplant
experiments and their non-tumorogenic safety profile. By expanding LT-HSC, the
use of UM171 allows clinicians to expand small cord units that hold the best
HLA matched CB to minimize complications, to ensure long-term engraftment in
vivo, and to increase both with better survival and quality of life. A full
description of the in vitro and in vivo experiments, including immune
reconstitution, pharmacokinetics, toxicity, and safety studies, conducted at
supra-elevated doses of UM171 is available in the ECT-001 Investigator*s
Brochure.
Study objective
This study has been transitioned to CTIS with ID 2024-517583-36-01 check the CTIS register for the current data.
Primary:
1) Examine the safety (including assessment of rate of graft failure) and
feasibility of infusing a single ECT-001-expanded cord blood in patients with
high and very high-risk acute leukemia/myelodysplasia
2) Evaluate relapse free survival at 1- and 2-years post-transplant in a group
of patients with high risk acute leukemia/myelodysplasia
Secondary:
1) Determine the kinetics of hematologic engraftment (including neutrophil and
platelet engraftment) following infusion of a single ECT-001-expanded cord
blood.
2) Estimate the incidence of transplant related mortality at day 100 and 1-year
post-transplant.
3) Determine incidence of acute and chronic GVHD by NIH criteria at 2 years
post-transplant
4) Determine incidence of grade 3 or higher infectious complications
5) Determine incidence of pre-engraftment/engraftment syndrome requiring
therapy
Study design
Prospective, single arm, open label, multi-center, non-randomized phase II
trial.
Intervention
The expansion and transplantation procedure can be summarized as follows:
The cord to be expanded is thawed about 15 days prior to transplant and
undergoes CD34+ selection. The CD34- product is cryopreserved and will be
thawed and infused on Day 0 (day of transplant). The CD34+ product will be
placed in culture with UM171 for a 7-day expansion, cryopreserved and will be
thawed and infused on Day 0. If the expanded cord or/and CD34- components do
not meet release criteria, an unmanipulated cord will be infused.
There are two preparative conditioning regimens allowed per protocol:
• Regimen A: High dose consisting of 1320 cGy TBI + Fludarabine +
Cyclophosphamide (18 to < 45 years old)
• Regimen B: Intermediate dose consisting of 400 cGy TBI + Fludarabine +
Cyclophosphamide + Thiotepa (18 to < 70 years old).
Patients will receive standard supportive care, growth factors and GVHD
prophylaxis (tacrolimus and MMF)
Study burden and risks
see protocol 4.4 Potential risks and benefits of ECT-001-CB expansion
Chemin de Polytechnique 2950
Montreal H3T 1J4
CA
Chemin de Polytechnique 2950
Montreal H3T 1J4
CA
Listed location countries
Age
Inclusion criteria
1) Age 18 to 65 years old
2) Presence of a high and very high-risk hematologic malignancy defined as:
a. Acute Myeloid Leukemia:
i. Primary induction failure (no CR or CRi after >= 2 courses of intensive
induction therapy or after >= 1 induction containing high dose Ara-C)
ii. Chemorefractory relapse (no CR or CRi after 1 chemointensive treatment)
iii. Relapse after allogeneic or autologous transplant.
iv. High risk AML in CR1 as defined by European Leukemia Net (ELN)
v. >= CR2
vi. Presence of minimal residual disease at the time of transplant63
b. Acute Lymphoid leukemia
i. Primary induction failure (>= 2 inductions)
ii. High risk ALL in CR1: Ph like ALL or any other poor risk feature
iii. >= CR2
iv. Chemorefractory relapse (at least 1 intensive induction chemotherapy)
v. Relapse after allogeneic or autologous transplant
vi. Presence of minimal residual disease at the time of transplant
c. Myelodysplastic syndrome (MDS):
i. Relapse after allogeneic or autologous transplant
ii. >=10 % blasts within 30 days of start of conditioning regimen
iii. Poor and very poor cytogenetics abnormalities
iv. CMML with HCT-specific CPSS score high or intermediate-264,65
v. Stable disease (absence of CR/PR/HI) after 6 cycles of azacitidine (or
another demethylating agent) 66,67.
vi. Progressive disease while on azacitidine (or another demethylating
agent)66-68.
d. Chronic myelogenous leukemia: Patients who have progressed to blast crisis.
3) Availability of 2 UCBs >= 4/6 HLA match when DRB1 is performed at the allele
level and A, B at antigen resolution (intermediate resolution) and >= 4/8 HLA
match when A, B, C and DRB1 are performed at the allele level. An acceptable
alternative would be a 3/6 or 5/8 as long as there is no double DRB1 mismatch.
a. Selection of cord to be expanded:
i. Pre-freeze CD34+ cell count >=0.5 x 105/kg and TNC>=1.5 x 107/kg
ii. Needs to be erythrodepleted by bank prior to cryopreservation
iii. Must come from a cord bank that is FACT or AABB accredited, FDA approved
or eligible for NMDP IND (unless PI approves another bank).
b. Selection of non-expanded CB/back-up cord:
i. Pre-freeze CD34+ cells >=1.5 x 105/kg with TNC count >= 2.0 x 107/kg or,
ii. Pre-freeze CD34+ cells >=1.7 x 105/kg with TNC count >=1.5 x 107 kg.
iii. If a single cord does not meet these criteria, 2 back up cords will be an
acceptable alternative with each having CD34+ cells >1 x 105/kg with TNC>1.5 x
107/kg
iv. Must come from a cord bank that is FACT or AABB accredited, FDA approved or
eligible for NMDP IND (unless PI approves another bank).
4) Karnofsky >=70.
5) Left ventricular ejection fraction >= 40% (within 3 months unless the patient
has received chemotherapy or radiation therapy to the thorax since the last
cardiac evaluation) OR fractional shortening >22%
6) Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and
diffusing capacity corrected for hemoglobin (DLCOc) >= 50% of predicted
7) Bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to
Gilbert*s disease or hemolysis; AST and ALT <= 2.5 x ULN; alkaline phosphatase <=
5 x ULN.
8) Adequate renal function defined as creatinine < 2.0 mg/dl. All patients with
a creatinine > 1.2 or a history of renal dysfunction must have estimated
creatinine clearance > 50 ml/min.
9) Hematopoietic cell transplantation specific comorbidity index (HCT-CI) <=3 if
patients have >=5% blasts in the bone marrow and HCT-CI <=5 if 60-65 years old.
Exclusion criteria
1) Allogeneic myeloablative transplant within 6 months.
2) Autologous hematopoietic stem cell transplant within 6 months.
3) Active or recent (prior 6 months) invasive fungal infection without ID
consult and approval.
4) The presence of a malignancy other than the one for which the UCB transplant
is being performed and the expected survival related to the malignancy is
estimated to be less than 75% at 5 years.
5) HIV positivity.
6) Hepatitis B or C infection with measurable viral load.
7) Liver cirrhosis.
8) Pregnancy, breastfeeding or unwillingness to use appropriate contraception.
9) Participation in a trial with an investigational agent within 30 days prior
to entry in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-517583-36-01 |
| EudraCT | EUCTR2022-002458-26-NL |
| ClinicalTrials.gov | NCT04103879 |
| CCMO | NL81857.000.22 |