Clinical trial NCT03441958: ECT-001 (UM171) Expanded Cord Blood Transplant to Treat High-risk Multiple Myeloma
Official title: A Phase I-II Open-label Study of Reduced Intensity-allogeneic Transplant of ECT-001 (UM171/ Fed-batch Culture System) Expanded Cord Blood in Patients With High-risk Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: hematopoietic stem cell transplant
Expanded cord blood
Lead sponsor: Ciusss de L'Est de l'Île de Montréal
Sponsor class: OTHER
Collaborators: name: ExCellThera inc.
name: Centre C3i
First posted: 2018-02-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Multiple Myeloma (MM) is a morbid disease associated with a poor outcome and while current therapies with new drugs have improved survival, MM still remains incurable in most patients. The only potential curative treatment remains allogeneic Hematopoietic stem cell transplant (HSCT), as shown by our cohort of 92 newly diagnosed patients who received a sibling tandem auto-allo (HSCT) with an estimated 10-year progression free survival (PFS) of 43%. However, the high incidences of toxicities including chronic graft-versus-host-disease (GVHD) (up to 79%) and disease progression (up to 49%) impair improvement in cure rate. Using umbilical cord blood (CB) as an alternative source of hematopoietic stem cells (HSC) could be superior biologically because of their increased proliferative capacity, greater number of progeny with longer telomeres and better anti-tumor efficacy in presence of positive residual disease. Moreover, using CB has been shown to decrease incidence of chronic GVHD. However, CBs have the disadvantage of having a limited HSC dose leading to prolonged cytopenia and higher risk of infections.

In a first in-human trial using CB expanded with the ECT-001 (UM171) molecule (clinicaltrial.gov # NCT02668315), the median net expansion of HSC was 36 fold, which allows for the selection of better HLA matched CB regardless of their lower HSC dose. Moreover, the ECT-001 expanded CBs have a different cell composition than regular CBs, with more than 25% of dendritic cell precursors. This, combined to better HLA matched CBs, may reduce chronic GVHD incidence and improve immune reconstitution. To date, 22 patients received an ECT-001 expanded CB and the procedure proved to be safe and feasible.

In this new trial, the goal is to evaluate the safety and efficacy of ECT-001 expanded CB transplant in high risk MM patients.

Detailed description: This is a single institution, prospective, phase I/II open-label study in a maximum of 20 patients evaluating a novel treatment strategy in NDMM patients with high-risk disease who do not have a 6/6 compatible sibling donor. Participating patients will be from Hôpital Maisonneuve-Rosemont (HMR) or referred to HMR for this protocol. Newly diagnosed multiple myeloma patients will be evaluated for eligibility before or during the autologous stem cell transplant (ASCT) period. After a Bortezomib-based induction treatment (VTD, CyBorD, RVD or PAD \[in patients with plasma cell leukemia\]) for a minimum of 4 cycles, followed by Melphalan ≥ 140 mg/m2 and ASCT, eligible patients who accept to participate will undergo screening evaluation to receive a Reduced Intensity (RIC) allogeneic HSCT with ECT-001 expanded CB. It is estimated that 18 months will be necessary to enroll the targeted sample size.

Once eligibility has been confirmed, study treatment will begin. After an ASCT, eligible patients will receive a conditioning regimen before receiving a RIC allogeneic HSCT with an ECT-001 expanded CB on day 0. Patients will be followed at least every week for the first 3 months, then every month, in the absence of GVHD, for disease evaluation and adverse events. Occurrence and severity of acute GVHD will be evaluated using the modified Glucksberg176 and IBMTR177 criteria, while chronic GVHD will be evaluated using the NIH178 criteria.

The trial will be terminated when all patients have been followed for 5 years after allogeneic HSCT.

Eligibility criteria: Inclusion Criteria:

1. Age 18-65 years.
2. Newly diagnosed multiple myeloma using the International Myeloma Working Group criteria with measurable disease and any of the following:

   i. t(4;14), t(14;16), t(14;20), del(17p13), chromosome 1 abnormalities with ISS II or III; ii. Revised-ISS 3; iii. Primary plasma cell leukemia; iv. Refractory to first line triplet Bortezomib-based induction treatment. v. ≥ 2 cytogenetics abnormalities as defined above regardless of ISS stage
3. Received a first line triplet Bortezomib-induction regimen for a minimum of 4 cycles with achievement of at least partial response; or received a doublet or triplet Lenalidomide-based second line induction treatment with at least partial response for patients refractory to Bortezomib in first line.
4. Received high-dose Melphalan ≥ 140 mg/m2 followed by ASCT.
5. Availability of a cord blood with an HLA match ≥ 5/8 and \< 8/8 meeting the following requirements: CD34+ cell count ≥ 0.5 x 105/kg and nucleated cell count \>= 1.5 x 107/kg.

Exclusion Criteria:

1. Having previously received two ASCT.
2. Having previously received autologous-allogeneic tandem transplantation.
3. Having received more than 4 months of maintenance with Lenalidomide or Bortezomib after ASCT.
4. Poor organ function defined as either: forced vital capacity, forced expiratory volume in 1 second or lung diffusing capacity of carbon monoxide corrected for hemoglobin \< 50%, left ventricular ejection fraction \< 40% (evaluated by either echocardiogram or MUGA), uncontrolled arrhythmia or symptomatic cardiac disease, creatinine clearance \< 60 mL/minute.
5. Karnofsky score \< 70% or comorbidity index HCT-CI \> 3.
6. 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; liver cirrhosis.
7. Non secretory disease or non-measurable disease in serum or urine at time of diagnosis.
8. Uncontrolled infection.
9. Active infection with any of the following viruses: HIV, HTLV-1 or 2, hepatitis B or C.
10. Presence of another malignancy with an expected survival estimated \< 75% at 5 years.
11. Suspicion of cardiac amyloidosis.
12. Current history of drug and/or alcohol abuse.
13. Availability of a matched sibling donor.
14. Pregnancy, breastfeeding or unwillingness to use appropriate contraception.
15. Participation in a trial with an investigational agent within 30 days prior to entry in the study.
16. Patient unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up and tests.
17. Any abnormal condition or laboratory result that is considered by the principal investigator capable of altering patient's condition or study outcome.

Primary outcomes:
measure: Safety of ECT-001 expanded CB expansion as measured by toxicity evaluation
timeFrame: 5 years
measure: Feasibility of ECT-001 expanded CB expansion
timeFrame: 5 years
measure: Measure of the kinetics of donor lymphoid cells recovery
timeFrame: 2 years
measure: Measure of the kinetics of donor myeloid cells recovery
timeFrame: 2 years
measure: Incidence of chronic GVHD by grade at 1 years by NIH criteria.
timeFrame: 1 year
measure: Incidence of chronic GVHD by grade at 2 years by NIH criteria.
timeFrame: 2 years
Secondary outcomes:
measure: Correlation between neutrophil and CD34+ doses infused
timeFrame: 2 years
measure: Correlation between neutrophil and CD34+CD45RA+ doses infused
timeFrame: 2 years
measure: Incidence of graft failure
timeFrame: 2 years
measure: Evaluation of T Cells reconstitution
timeFrame: 3 years
measure: Evaluation of B cells reconstitution
timeFrame: 3 years
measure: Evaluation of NK Cells reconstitution
timeFrame: 3 years
measure: Evaluation of expanded HSC activity in vivo
timeFrame: 3 years
measure: Incidence of acute GVHD at day +120
timeFrame: 4 months
measure: Incidence of acute GVHD at 6 month
timeFrame: 6 months
measure: Incidence of acute GVHD at 1 year
timeFrame: 1 year
measure: Incidence of grade >=3 infectious complications
timeFrame: 5 years
measure: Incidence of engraftment syndrome requiring therapy
timeFrame: 2 years
measure: Duration of hospitalization
timeFrame: 6 months
measure: Non relapse mortality at day +120
timeFrame: 4 months
measure: Non relapse mortality at 1 year
timeFrame: 1 year
measure: Non relapse mortality at 2 year
timeFrame: 2 years
measure: Progression free survival at 2 years
timeFrame: 2 years
measure: Overall survival at 2 years
timeFrame: 2 years
measure: Response to treatment at 1 year after allogeneic transplant
timeFrame: 1 years
measure: Response to treatment at 2 year after allogeneic transplant
timeFrame: 2 years
measure: Best response achieve at 1 year after allogeneic transplant
timeFrame: 1 years
measure: Best response achieve at 2 year after allogeneic transplant
timeFrame: 2 years
measure: Minimal residual disease post transplant
timeFrame: 5 years
measure: Patient's quality of life
timeFrame: 5 years
measure: Pharmaco-economic evaluation of the proposed treatment
timeFrame: 5 years
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: CIUSSS de l'Est-de-l'île-de-Montréal, Installation Hôpital Maisonneuve Rosemond
state: Quebec
Study officials:
affiliation: Ciusss de L'Est de l'Île de Montréal
name: Jean Roy, MD
role: PRINCIPAL_INVESTIGATOR
References: