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Co-infusion of haematopoietic stem cells from a haplo-identical donor and single unit unrelated cord blood in patients with a high risk of relapse: A Phase l/ll study to assess safety and to investigate the biological mechanism of the anti-tumor response.


- candidate number10384
- NTR NumberNTR3079
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR24-sep-2011
- Secondary IDs11-313 METC UMCU
- Public TitleCo-infusion of haematopoietic stem cells from a haplo-identical donor and single unit unrelated cord blood in patients with a high risk of relapse: A Phase l/ll study to assess safety and to investigate the biological mechanism of the anti-tumor response.
- Scientific TitleCo-infusion of haematopoietic stem cells from a haplo-identical donor and single unit unrelated cord blood in patients with a high risk of relapse: A Phase l/ll study to assess safety and to investigate the biological mechanism of the anti-tumor response.
- ACRONYMHaploCord
- hypothesisTo study the safety of co-infusion of a T-/CD19 B-cell depleted haematopoietic stem cells from haplo-identical donor and a single unit cord blood unit and to investigate the anti-tumor responses from both grafts.
- Healt Condition(s) or Problem(s) studiedAllogeneic stem cell transplantation, Umbilical cord blood, Haplo identical, High risc hematological disease
- Inclusion criteria1. Patients with either:
A. No standard HSCT protocol available and any of the following malignancies: NHL or HD (refractory, ≥2CR); relapse AML/refractory AML, MDS, SAA, ALL ≥CR2;
B. Relapse after first allo-HSCT with either SIB or MUD/UCB donor;
C. With a leukemia/lymphoma indication, qualifying for HSCT but without donor available according to ongoing, open study protocols no fully matched family donor or matched (9-10/10) unrelated donor available and / or no single or double unit cord blood available with sufficient cell numbers according to ongoing, open study protocols.
2. With having a single matching (≥ 4/6) umbilical CB unit available with total NC count > 1,5 E7/kg;
3. Lansky / Karnofsky > 40;
4. Age 18-65 * (*= age ≤ 65 and 364 days);
5. Signed Informed Consent.
- Exclusion criteria1. Creatinine clearance < 40 ml/min;
2. Cardiac dysfunction (SF < 30%) (Ejection fraction < 45%), unstable angina, or unstable cardiac arrhythmias;
3. Pulmonary function test VC, FEV1 and/ or DOC< 50%.
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-nov-2011
- planned closingdate1-nov-2016
- Target number of participants37
- InterventionsFor a group of patients with a very high risk malignancy: Instead of using a single donor, or no transplantation at all, a combination of a cord blood unit and selected cells from a haplo-identical family-donor are infused at the day of transplant. The selection procedure of the haplodonor allows mismatch NK-cells and T-cells in the graft for extra anti-tumor effect.
- Primary outcomeSafety: Transplantation related (non-relapse) mortality (TRM).
Biology: Investigate the anti-tumor response mechanism from both grafts.
- Secondary outcome1. Acute- GVHD ( Grade II-IV: Gluckberg Criteria);
2. Engraftment: Neutrophils > 500K/uL for 3 consecutive days and Platelet (day 180 > 50 K) engraftment;
3. Loss of CB chimerism (<25%) at 6 mths post HSCT;
4. Event Free Survival (>6 mths follow up). Event defined as: Death, graft-failure (<25% total donor chimerism) or relapse;
5. Non-Relapse Mortality;
6. Overall Survival;
7. Chronic GVHD: Limited and extensive (Shulman Criteria);
8. VOD (Seattle Criteria);
9. Mucositis ≥ CTC grade 3.
- TimepointsT= 0 is inclusion till 12 months after allogeneic stem cell transplantation.
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIESDr. J.H.E. Kuball
- CONTACT for SCIENTIFIC QUERIESDr. J.H.E. Kuball
- Sponsor/Initiator University Medical Center Utrecht (UMCU)
- Funding
(Source(s) of Monetary or Material Support)
University Medical Center Utrecht (UMCU)
- PublicationsN/A
- Brief summaryAlthough haematopoietic stem cells transplantation (HSCT) has become much safer over the last decade the major limitation remain “transplantation related mortality (TRM; e.g. due to viral reactivations/disease)” and relapse (in malignancies). Within the group of malignancies there is a subgroup of patients with a ”very high risk (of relapse) profile” (e.g. relapse AML, refractory lymphoma, relapse after first allo-HSCT). Although this “very high risk group” may potentially benefit from allo-HSCT with the currently available “standard” transplant protocols the expected survival rates are very low <20%. Cord blood (CB) is emerging as stem cell source for HSCT because it has many advantages above the conventional bone marrow grafts. Disadvantages are however low stem cell count/kg for adults associated with prolonged neutropenia and a slower T cell recovery. T cell depleted haplo-grafts have the advantage of early neutrophil engraftment but are associated with higher rates of secondary graft-failure and poor T-cell reconstitution associated with viral infections. KIR-mismatching in Haplo-grafting is suggested to have anti-leukemic potential.

RATIONALE:
Combining cord blood and readily available haplo-identical family donor-HSCT combines beneficial effects of both allogeneic transplantations strategies, such as the in the long term excellent T-cell recovery after CB HSCT, and the NK-cell mediated anti-tumor activity of CB with the early haplo-mediated neutrophil recovery and the targeted anti-leukemia effect of NK (KIR mismatch) and T-cells after selected haplo-HSCT. We propose therefore that this multimodal treatment protocol may be a treatment option in the selected group of patients with a “very high risk (on relapse) profile”. These patients with the very high risk profile may profit for from this double grafting because of:
Multi-modal cellular therapy: Strong early (first 2-4 weeks) NK + T-cells mediated anti-tumor activity from the haplo-graft and NK + T-cellular anti-tumor activity (> 4 weeks) from the CB-graft, without increasing the risk of aGVHD.

OBJECTIVE:
To study the safety of co-infusion of a T-/CD19 B-cell depleted haematopoietic stem cells from haplo-identical donor and a single unit cord blood unit and to investigate the anti-tumor responses from both grafts.

STUDY DESIGN:
Prospective study, Phase l/ll trial with an optimal 2-stage design.
- Main changes (audit trail)
- RECORD24-sep-2011 - 26-okt-2011


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