A Study of CD45RA+ Depleted Haploidentical Stem Cell Transplantation in Children With Relapsed or Refractory Solid Tumors and Lymphomas

Sponsor

St. Jude Children's Research Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01625351

Collaborator

CURE Childhood Cancer, Inc. (Other)

Enrollment

Location

Arm

89.7

Actual Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase I study designed to determine the feasibility of transplantation using a novel transplant approach that employs a two-stage haploidentical cell infusion following myeloablative conditioning. This strategy, which includes selective depletion of naïve T cells, may speed immune reconstitution thereby potentially reducing the limitations of traditional haploidentical hematopoietic stem cell transplantation (HSCT) and increasing its potential therapeutic application. Additionally, the investigators intend to explore overall survival, event-free survival, hematopoietic cell recovery and engraftment as well as infection rates and complications in these patients.

Condition or Disease	Intervention/Treatment	Phase
Ewing Sarcoma Gastrointestinal Tumor Germ Cell Tumor Hepatic Tumor Lymphoma Wilms Tumor Rhabdoid Tumor Clear Cell Carcinoma Renal Cell Carcinoma Melanoma Neuroblastoma Rhabdomyosarcoma Non-rhabdomyosarcoma	Drug: alemtuzumab Drug: fludarabine Drug: sirolimus Drug: Busulfan Drug: melphalan Biological: stem cells Device: CliniMACS	Phase 1

Detailed Description

Twelve participants and 12 donors will be enrolled on this study. Donors will undergo seven days of hematopoietic stem cell (HSC) mobilization followed by two apheresis collections. Each apheresis collection will be processed by the CliniMACS system.

DONORS: A mobilization regimen of granulocyte colony stimulating factor (G-CSF) will be used to obtain a peripheral blood stem cell (PBSC) product from the donor. Apheresis will be performed for a minimum of two consecutive days, including one day for each cell product delivered.

STUDY PARTICIPANTS: Participants will undergo a two-stage haploidentical cell infusion following myeloablative conditioning. The first cell infusion will be a CD3-depleted product and the second infusion will be a CD45RA-depleted product.

Primary Objective:

To determine the feasibility of haploidentical HSCT using two infusions engineered by negative selection on the Miltenyi CliniMACS system- the first by selective depletion of CD3+ cells, followed by a second depleted of CD45RA+ cells, in children with relapsed or refractory solid tumors or lymphomas.

Secondary Objectives:

To estimate hematopoietic cell recovery and engraftment rates for the patients.
To estimate infection rates and complications.
To estimate the one-year overall survival (OS) and event-free survival (EFS) for the study patients.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of CD45RA+ Depleted Haploidentical Stem Cell Transplantation in Children With Relapsed or Refractory Solid Tumors and Lymphomas

Actual Study Start Date :

Aug 20, 2012

Actual Primary Completion Date :

Feb 10, 2020

Actual Study Completion Date :

Feb 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Participants to undergo transplantation. They receive alemtuzumab, fludarabine, sirolimus, busulfan, melphalan, and stem cells. Participants treated after activation of protocol revision 2.3 on 06/05/2014 have not and will not receive sirolimus as part of their therapy. Cells for infusion are prepared using the CliniMACS System.	Drug: alemtuzumab Patients receive alemtuzumab on days -14 through -12 (Day 0 = stem cell transplantation). Other Names: CAMPATH-1H Campath(R) Drug: fludarabine Patients receive fludarabine phosphate on days -11 through -7. (Day 0 = stem cell transplantation.) Other Names: Fludara(R) Drug: sirolimus Patients receive sirolimus beginning on day -1 with taper beginning on day 90. (Day 0 = stem cell transplantation.) Participants treated after activation of protocol revision 2.3 on 06/05/2014 have not and will not receive sirolimus as part of their therapy. Other Names: Rapamycin Rapamune(R) Drug: Busulfan Patients receive busulfan on days -6 through -3. (Day 0 = stem cell transplantation.) Other Names: Busulfex(R) Myleran(R) Drug: melphalan Patients receive melphalan on days -2 and -1. (Day 0 = stem cell transplantation.) Other Names: L-phenylalanine mustard phenylalanine mustard L-PAM L-sarcolysin Biological: stem cells Patients undergo CD3 depleted haploidentical hematopoietic stem cell transplant (HSCT) on day 0. Patients also undergo CD45RA depleted HSCT infusion on day 1. (Day 0 = stem cell transplantation.) Other Names: HSCT Stem cell transplantation Device: CliniMACS The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells. Other Names: Cell Selection System

Arm

Intervention/Treatment

Experimental: Treatment

Participants to undergo transplantation. They receive alemtuzumab, fludarabine, sirolimus, busulfan, melphalan, and stem cells. Participants treated after activation of protocol revision 2.3 on 06/05/2014 have not and will not receive sirolimus as part of their therapy. Cells for infusion are prepared using the CliniMACS System.

Drug: alemtuzumab

Patients receive alemtuzumab on days -14 through -12 (Day 0 = stem cell transplantation).

Other Names:

CAMPATH-1H

Campath(R)

Drug: fludarabine

Patients receive fludarabine phosphate on days -11 through -7. (Day 0 = stem cell transplantation.)

Other Names:

Fludara(R)

Drug: sirolimus

Patients receive sirolimus beginning on day -1 with taper beginning on day 90. (Day 0 = stem cell transplantation.) Participants treated after activation of protocol revision 2.3 on 06/05/2014 have not and will not receive sirolimus as part of their therapy.

Other Names:

Rapamycin

Rapamune(R)

Drug: Busulfan

Patients receive busulfan on days -6 through -3. (Day 0 = stem cell transplantation.)

Other Names:

Busulfex(R)

Myleran(R)

Drug: melphalan

Patients receive melphalan on days -2 and -1. (Day 0 = stem cell transplantation.)

Other Names:

L-phenylalanine mustard

phenylalanine mustard

L-PAM

L-sarcolysin

Biological: stem cells

Patients undergo CD3 depleted haploidentical hematopoietic stem cell transplant (HSCT) on day 0. Patients also undergo CD45RA depleted HSCT infusion on day 1. (Day 0 = stem cell transplantation.)

Other Names:

HSCT

Stem cell transplantation

Device: CliniMACS

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

Other Names:

Cell Selection System

Outcome Measures

Primary Outcome Measures

Feasibility of haploidentical HSCT [30 days post transplantation]
Feasibility is defined as engraftment (ANC≥ 500/mm3 for 3 consecutive tests performed on different days) evaluated before day +30.

Secondary Outcome Measures

hematopoietic cell recovery and engraftment rates [30 days post transplantation]
They will be reported and presented descriptively. Specifically, the hematopoietic cell recovery and engraftment rates will be reported with a Blyth-Still-Casella 95% confidence interval.
infection rates and complications [up to 5 years]
The proportion of patients who develop infections and complications will be estimated and a Blyth-Still-Casella 95% confidence interval will be provided.
overall survival (OS) [up to 1 year after transplantation]
Defined based on any death. The Kaplan-Meier Estimate will be provided.
event-free survival [up to 1 year after transplantation]
The Kaplan-Meier Estimate will be provided.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria - Transplant Recipients:

At least 2 years of age and less than or equal to 21 years of age.
Histologically confirmed solid tumor or lymphoma at original diagnosis:
Ewing Sarcoma Family of Tumors (ESFT)
Gastrointestinal tumors
Germ Cell tumors
Hepatic tumors (including hepatocellular carcinoma and hepatoblastoma)
Lymphoma (including Hodgkin and non-Hodgkin lymphoma)
Kidney tumors (including Wilms tumor, rhabdoid tumors, clear cell carcinoma, and renal cell carcinoma)
Melanoma
Neuroblastoma
Soft tissue sarcoma (including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma)
Malignancy has no reasonable expectation of cure with available alternative salvage therapy.
Has a suitable human leukocyte antigen (HLA) haploidentical donor available.
At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation therapy.
Has recovered from all acute NCI Common Toxicity Criteria grade II-IV acute non-hematologic toxicities from prior therapy per the judgment of the PI.
Shortening fraction greater than or equal to 25%.
Creatinine clearance or glomerular filtration rate (GFR) greater than or equal to 50 mL/min/1.73 m2.
Pulse oximetry greater than or equal to 92% on room air
Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to3 times the upper limit of the institution-established normal range.
Direct bilirubin less than or equal to 3.0 mg/dL.
Karnofsky or Lansky performance score of greater than or equal to 50.

Exclusion Criteria - Transplant Recipients:

Newly diagnosed patients with no prior attempt at curative therapy.
Any primary or active central nervous system (CNS) malignancy, including metastatic disease.
Any active or prior malignant or pre-malignant condition of the bone marrow, excluding metastasis of the primary malignancy.
Prior allogeneic hematopoietic stem cell transplant.
Prior autologous stem cell transplant within previous 3 months.
Allergy to murine products or positive human anti-mouse antibody (HAMA).
(Female only) Known pregnancy (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
(Female only) Breast feeding.

Inclusion Criteria - Donors:

At least 18 years of age.
Partially HLA matched family member.
Human immunodeficiency virus (HIV) negative.

Exclusion Criteria - Donors:

(Female only) Known pregnancy (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
(Female only) Breast feeding.