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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Measure of the kinetics of donor myeloid cells recovery
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-65 years.
- •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
- •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.
- •Received high-dose Melphalan ≥ 140 mg/m2 followed by ASCT.
- •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.
排除标准
- •Having previously received two ASCT.
- •Having previously received autologous-allogeneic tandem transplantation.
- •Having received more than 4 months of maintenance with Lenalidomide or Bortezomib after ASCT.
- •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.
- •Karnofsky score < 70% or comorbidity index HCT-CI >
- •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.
- •Non secretory disease or non-measurable disease in serum or urine at time of diagnosis.
- •Uncontrolled infection.
- •Active infection with any of the following viruses: HIV, HTLV-1 or 2, hepatitis B or C.
- •Presence of another malignancy with an expected survival estimated < 75% at 5 years.
- •Suspicion of cardiac amyloidosis.
- •Current history of drug and/or alcohol abuse.
- •Availability of a matched sibling donor.
- •Pregnancy, breastfeeding or unwillingness to use appropriate contraception.
- •Participation in a trial with an investigational agent within 30 days prior to entry in the study.
- •Patient unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up and tests.
- •Any abnormal condition or laboratory result that is considered by the principal investigator capable of altering patient's condition or study outcome.
研究组 & 干预措施
ECT-001 (UM171) expanded cord blood
- Patients will receive a reduced intensity conditioning regimen containing Cyclophosphamide 50 mg/kg, Fludarabine 40 mg/m2 x 5 days and total body irradiation 200 cGy.
- The cord to be expanded is thawed 7 days prior to transplant and undergoes CD34+ selection. The CD34+ product will be placed in the fed-batch culture with UM171 for a 7-day expansion and is infused fresh on Day 0. The CD34- product is cryopreserved and will be thawed and infused on Day +1.
- Patients will receive standard supportive care and GVHD prophylaxis with Mycophenolate mofetil and Tacrolimus.
干预措施: ECT-001 (UM171) expanded cord blood (Biological)
结局指标
主要结局
Measure of the kinetics of donor myeloid cells recovery
时间窗: 2 years
Time to neutrophils and platelets engraftment will be measured
Incidence of chronic GVHD by grade at 1 years by NIH criteria.
时间窗: 1 year
The incidence of chronic GVHD will be evaluated at 1 years using the recommendations of the NIH Consensus Conference and recently updated. Analysis by cumulative incidence
Feasibility of ECT-001 expanded CB expansion
时间窗: 5 years
Number of successful expansion and infusions in an outpatient nonmyeloablative transplant condition for high-risk myeloma patients
Safety of ECT-001 expanded CB expansion as measured by toxicity evaluation
时间窗: 5 years
AEs with a CTCAE grade ≥ 3 (non hematologic) and with a grade ≥ 4 (hematologic) will be reported from the beginning of the conditioning regimen up to 5 years after CB transplant.
Measure of the kinetics of donor lymphoid cells recovery
时间窗: 2 years
Donor lymphocytes cells recovery assessed by chimerism analysis.
Incidence of chronic GVHD by grade at 2 years by NIH criteria.
时间窗: 2 years
The incidence of chronic GVHD will be evaluated at 1 years using the recommendations of the NIH Consensus Conference and recently updated. Analysis by cumulative incidence
次要结局
- Non relapse mortality at 1 year(1 year)
- Incidence of grade >=3 infectious complications(5 years)
- Non relapse mortality at 2 year(2 years)
- Progression free survival at 2 years(2 years)
- Incidence of engraftment syndrome requiring therapy(2 years)
- Incidence of acute GVHD at day +120(4 months)
- Correlation between neutrophil and CD34+CD45RA+ doses infused(2 years)
- Incidence of graft failure(2 years)
- Incidence of acute GVHD at 6 month(6 months)
- Incidence of acute GVHD at 1 year(1 year)
- Duration of hospitalization(6 months)
- Best response achieve at 2 year after allogeneic transplant(2 years)
- Patient's quality of life(5 years)
- Correlation between neutrophil and CD34+ doses infused(2 years)
- Evaluation of T Cells reconstitution(3 years)
- Evaluation of B cells reconstitution(3 years)
- Evaluation of NK Cells reconstitution(3 years)
- Evaluation of expanded HSC activity in vivo(3 years)
- Non relapse mortality at day +120(4 months)
- Overall survival at 2 years(2 years)
- Response to treatment at 1 year after allogeneic transplant(1 years)
- Pharmaco-economic evaluation of the proposed treatment(5 years)
- Response to treatment at 2 year after allogeneic transplant(2 years)
- Best response achieve at 1 year after allogeneic transplant(1 years)
- Minimal residual disease post transplant(5 years)
研究者
Jean Roy
MD
Ciusss de L'Est de l'Île de Montréal