CASPALLO: Allodepleted T Cells Transduced With Inducible Caspase 9 Suicide Gene

NCT00710892 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 21580-CASPALLO
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

Patients are being asked to participate in this study because they will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, they will be given very strong doses of chemotherapy, which will kill off all their existing stem cells. Stem cells are created in the bone marrow. They grow into different types of blood cells that we need, including red blood cells, white blood cells, and platelets. We have identified a close relative of the patients whose stem cells are not a perfect match for the patient, but can be used. This type of transplant is called "allogeneic", meaning that the cells come from a donor. With this type of donor who is not a perfect match, there is typically an increased risk of developing graft-versus-host disease (GvHD) and a longer delay in the recovery of the immune system. GvHD is a serious and sometimes fatal side effect of stem cell transplant. GvHD occurs when the new donor cells recognize that the body tissues of the patient are different from those of the donor. In the laboratory, we have seen that cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. To get the iCasp9 into the T cells, we insert it using a virus called a retrovirus that has been made for this study. The drug (AP1903) that will be used to "activate" the iCasp9 is an experimental drug that has been tested in a study in normal donors, with no bad side effects. We hope we can use this drug to kill the T cells. Other drugs that kill or damage T cells have helped GvHD in many studies. However we do not yet know whether AP1903 will kill T cells in humans, even though it has worked in our experimental studies on human cells in animals. Nor do we know whether killing the T cells will help the GvHD. Because of this uncertainty, patients who develop significant GvHD will also receive standard therapy for this complication, in addition to the experimental drug. We hope that having this safety switch in the T cells will let us give higher doses of T cells that will make the immune system recover faster. These specially treated "suicide gene" T cells are an investigational product not approved by the Food and Drug Administration.

Conditions

Acute Lymphoblastic Leukemia; Non-Hodgkin's Lymphoma; Myelodysplastic Syndrome; Chronic Myeloid Leukemia

Keywords

suicide gene-modified allodepleted donor lymphocytes; given to recipients of haploidentical stem cell transplants; Stage III; Stage IV; Myelodysplastic syndrome; AML after first relapse; primary refractory disease; CML; Hemophagocytic lymphohistiocytosis (HLH); familial hemophagocytic lymphohistiocytosis (FLH); viral-associated hemophagocytic syndrome (VAHS); Severe chronic active Epstein Barr virus infection (SCAEBV); T or NK cell malignancy; X-linked lymphoproliferative disease (XLP)

Outcome Measures

Primary Outcomes (1)

• To determine the maximum number of suicide gene-modified allodepleted donor lymphocytes that can be given to recipients of haploidentical stem cell transplants that will result in a rate of Grade III/IV GVHD of 25% or less.

  Maximum tolerated dose of suicide gene-modified allodepleted donor lymphocytes up to a total of 1 x 10e7/kg per dose.

  45 days

Secondary Outcomes (4)

• To evaluate the biological effects of administration of AP1903, a dimerizer used to activate the suicide gene mechanism, and its clinical effects in patients who develop GvHD.

  1 year

• To analyze the contribution of the gene-modified cells to immune reconstitution in these patients by measuring their survival, persistence and expansion.

  15 years

• To measure the overall and disease-free survival at 100 days and at 1 year post-transplant.

  1 year

• To obtain preliminary information on whether subjects receiving additional doses of cells show a cumulative rise in the percentage of circulating gene-modified cells.

  15 years

Study Arms (1)

Dose Level 1-3

EXPERIMENTAL

Administration of suicide gene-modified allodepleted T cells.

Biological: Allodepleted T Cells

Interventions

Allodepleted T Cells BIOLOGICAL

Dose Level 1 = 1 x 10e6 T cells/kg; Dose Level 2 = 3 x 10e6 T cells/kg; Dose Level 3 = 1 x 10e7 T cells/kg. Patients may be enrolled at the next dose level of T cells when all patients at the previous dose level have reached Day 42 post-T cell infusion without unacceptable toxicity.

Dose Level 1-3

Eligibility Criteria

• Age: Up to 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• At the time of transplant:
• A. Patients (up to 65 years of age) with:
• ALL or high grade NHL that is Stage III or IV and has relapsed or is considered to be primary refractory disease.
• Myelodysplastic syndrome.
• AML after first relapse or with primary refractory disease.
• CML
• Hemophagocytic lymphohistiocytosis (HLH); familial hemophagocytic lymphohistiocytosis (FLH); viral-associated hemophagocytic syndrome (VAHS); patients with severe chronic active Epstein Barr virus infection (SCAEBV) with predilection for T or NK cell malignancy; X-linked lymphoproliferative disease (XLP)
• B. Lack of suitable conventional donor (i.e. 5/6 or 6/6 related, or 5/6 or 6/6 unrelated donor) or presence of a rapidly progressive disease not permitting time to identify an unrelated donor.
• At the time of allodepleted T cell infusion:
• Engrafted with ANC greater than 500.
• Must have greater than or equal to 50% donor chimerism in either peripheral blood or bone marrow, or relapse of their original disease.
• Life expectancy greater than 30 days
• Lansky/Karnofsky scores greater than or equal to 60
• Absence of severe renal disease (creatinine greater than 2X normal for age)
• Absence of severe hepatic disease (direct bilirubin greater than 2 mg/dL, or SGOT greater than 200

You may not qualify if:

• At the time of transplant:
• \. Pregnancy\*
• At the time of allodepleted T cell infusion:
• GvHD
• Severe intercurrent infection
• Pregnancy\*
• Other investigational drugs in the prior 30 days
• Pregnancy test only required for at-risk individuals, defined as female patients of childbearing potential who have received a reduced-intensity conditioning regimen.

Sponsors & Collaborators

• Baylor College of Medicine: lead
• The Methodist Hospital Research Institute: collaborator
• Center for Cell and Gene Therapy, Baylor College of Medicine: collaborator

Study Sites (2)

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

The Methodist Hospital

Houston, Texas, 77030, United States

Location

Related Publications (4)

• Chang EC, Liu H, West JA, Zhou X, Dakhova O, Wheeler DA, Heslop HE, Brenner MK, Dotti G. Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch. Mol Ther. 2016 Apr;24(4):736-45. doi: 10.1038/mt.2015.217. Epub 2015 Dec 7.

  PMID: 26639404 DERIVED

• Zhou X, Di Stasi A, Brenner MK. iCaspase 9 Suicide Gene System. Methods Mol Biol. 2015;1317:87-105. doi: 10.1007/978-1-4939-2727-2_6.

  PMID: 26072403 DERIVED

• Zhou X, Di Stasi A, Tey SK, Krance RA, Martinez C, Leung KS, Durett AG, Wu MF, Liu H, Leen AM, Savoldo B, Lin YF, Grilley BJ, Gee AP, Spencer DM, Rooney CM, Heslop HE, Brenner MK, Dotti G. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood. 2014 Jun 19;123(25):3895-905. doi: 10.1182/blood-2014-01-551671. Epub 2014 Apr 21.

  PMID: 24753538 DERIVED

• Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673-83. doi: 10.1056/NEJMoa1106152.

  PMID: 22047558 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Non-Hodgkin; Myelodysplastic Syndromes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphohistiocytosis, Hemophagocytic; Histiocytic Sarcoma; Lymphoproliferative Disorders

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma; Bone Marrow Diseases; Leukemia, Myeloid; Myeloproliferative Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Histiocytic Disorders, Malignant

Study Officials

• Malcolm K Brenner, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 3, 2008
• First Posted: July 8, 2008
• Study Start: December 1, 2008
• Primary Completion: November 1, 2011
• Study Completion (Estimated): July 1, 2026
• Last Updated: July 11, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)