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Donor Lymphocyte Infusion (DLI) of T-cells Genetically Modified With iCasp9 Suicide Gene

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01875237
Recruitment Status : Terminated
First Posted : June 11, 2013
Results First Posted : July 16, 2019
Last Update Posted : July 16, 2019
Sponsor:
Collaborator:
Bellicum Pharmaceuticals
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn if giving genetically changed immune cells, called T-cells, after chemotherapy will improve the response to a stem cell transplant. The safety of this treatment will also be studied.

The process of changing the DNA (the genetic material in cells) of these T-cells is called "gene transfer." Researchers want to learn if these genetically-changed T-cells are effective in attacking cancer cells in patients with leukemia, MDS, lymphoma, Hodgkin disease, or MM, after they have received an allogeneic stem cell transplant.

The chemotherapy you will be given on study is fludarabine, melphalan, and alemtuzumab. These drugs are designed to stop the growth of cancer cells, which may cause the cancer cells to die. This chemotherapy is also designed to block your body's ability to reject the donor's stem cells.

Researchers also want to learn if giving AP1903 will help the symptoms of graft-versus-host disease (GvHD) that may occur after the T-cell infusion. GvHD occurs when donor cells attack the cells of the person receiving the stem cell transplant.


Condition or disease Intervention/treatment Phase
Leukemia Myeloma Myeloproliferative Diseases Drug: Fludarabine Drug: Melphalan Drug: Alemtuzumab Procedure: Stem Cell infusion Drug: Tacrolimus Drug: Mini Methotrexate Drug: G-CSF Procedure: Donor Lymphocyte Infusion (DLI) Drug: AP1903 Drug: Methylprednisolone Behavioral: Questionnaire Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial Evaluating Treatment of Emergent Graft Versus Host Disease (GvHD) With AP1903 After Planned Donor Infusions (DLIs) of T-cells Genetically Modified With the iCasp9 Suicide Gene in Patients With Hematologic Malignancies
Actual Study Start Date : December 27, 2013
Actual Primary Completion Date : March 7, 2017
Actual Study Completion Date : March 7, 2017


Arm Intervention/treatment
Experimental: Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
Drug: Fludarabine
40 mg/m2 by vein on Days -6 to -3.
Other Names:
  • Fludarabine phosphate
  • Fludara

Drug: Melphalan
140 mg/m2 by vein on Day -2.
Other Name: Alkeran

Drug: Alemtuzumab
50 mg by vein on Day -1.
Other Names:
  • CAMPATH-1H
  • Campath

Procedure: Stem Cell infusion
Stem cell infusion on Day 0. Goal is to administer more than 3 x 10^6 CD34+ cells/kg of peripheral blood progenitor cells (PBPC).

Drug: Tacrolimus
Starting dose of 0.015 mg/kg (ideal body weight) as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml (target is 10 ng/ml) between Day +1 and Day +45. Tacrolimus is changed to oral dosing when tolerated. Tacrolimus tapering should start on approximately Day +35 with the intention for the patient to be completely off the drug by approximately Day +45.
Other Name: Prograf

Drug: Mini Methotrexate
5 mg/m2 by vein on Days +1, +3, +6.

Drug: G-CSF
5 mcg/kg/day subcutaneously beginning on Day +7, and continuing until the absolute neutrophil count (ANC) is > 500 x 10/L for 3 consecutive days.
Other Names:
  • Filgrastim
  • Neupogen

Procedure: Donor Lymphocyte Infusion (DLI)
iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64.

Drug: AP1903
0.4 mg/kg as a 2 hour infusion for patients that present with a clinical diagnosis of grade I GvHD. For patients with a clinical diagnosis of grade > 2 GvHD, a single dose of AP1903 0.4 mg/kg as a 2 hour infusion will be administered. Patients who fail to achieve a complete response within 72 hours of an initial dose of AP1903, or within 48 hours of a second dose of AP1903, will be maintained on this dose for no less than 7 days. Patients who experience a partial response within 72 hours may receive a second dose of AP1903. Patients whose GvHD is progressing after 7 days, have no response by 14 days, or are not in a complete response at day 28 can receive secondary therapy.

Drug: Methylprednisolone
1.6 mg/kg per day by vein divided in 2 to 3 daily doses. Patients whose GvHD resolves as defined by a complete response within 72 hours, would have steroids stopped immediately. Patients who fail to achieve a complete response within 72 hours of an initial dose of AP1903, or within 48 hours of a second dose of AP1903, will be maintained on this dose for no less than 7 days. Steroids can then be tapered as tolerated to no less than 0.6 mg/kg per day at day 28.
Other Names:
  • Depo-Medrol
  • Medrol
  • Solu-Medrol

Behavioral: Questionnaire
Completion of a quality of life questionnaire that will take 10-15 minutes between Days + 28 and + 56, about twice a week until about 2 months after the T-cell infusion, and then 6 and 12 months after the stem cell transplant.
Other Name: Survey




Primary Outcome Measures :
  1. To Evaluate the Safety of Donor Lymphocyte Infusion Followed by Dimerizer Drug, AP1903 by Number of Participants With Adverse Events. [ Time Frame: up to 3.5 years ]
    To evaluate the safety of the infusion of inducible caspase 9 (BPZ-1001) modified T-cells followed by dimerizer drug, AP1903. Safety evaluated by number of participants with Adverse events.


Secondary Outcome Measures :
  1. Number of Participants Assessed Post Donor Lymphocyte Infusion (DLI): Disease-free Survival & Non-relapse Mortality, Chimerism and GVHD. [ Time Frame: 6 months ]
    Participants to assess at 6 months post donor lymphocyte infusion (DLI): disease-free survival & non-relapse mortality, chimerism and GVHD

  2. To Assess the Incidence of Epstein-Barr Virus -PTLD or EBV Reactivation Requiring Therapy Post DLI. [ Time Frame: 1 year ]
    To assess the incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorder or EBV reactivation requiring therapy post DLI.

  3. To Assess the Proportion of Patients Developing Grade I-IV Acute GvHD [ Time Frame: Day 28, 56, and 180 post DLI. ]
    To assess the proportion of patients developing grade I-IV acute GvHD by Day 28, 56, and 180 post DLI.

  4. To Assess the Proportions of GvHD Response Post-administration of AP1903. [ Time Frame: Day 3, 7, 14, 28, and 56 post-administration of AP1903 ]
    To assess the proportions of GvHD complete response (CR), partial response (PR), mixed response, no response, and progression among surviving patients at Day 3, 7, 14, 28, and 56 post-administration of AP1903.

  5. To Assess the Incidence of GvHD Treatment Failure Post-administration of AP1903. [ Time Frame: Day 3, 7, 14, 28, and 56 post-administration of AP1903. ]
    To assess the incidence of GvHD treatment failure, defined as no response, progression, administration of additional therapy for GvHD, or mortality post-administration of AP1903.

  6. To Assess the Incidence of Acute GvHD Flare After CR/PR Requiring Additional Agent for Systemic Therapy Before Day 56 Post-administration of AP1903. [ Time Frame: before Day 56 post AP1903 ]
    To assess participants with incidence of acute GvHD flare after CR/PR requiring additional agent (including 2.5 mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) for systemic therapy before Day 56 post-administration of AP1903."

  7. To Assess Post Donor Lymphocyte Infusion (DLI) Chimerism [ Time Frame: 6 months ]
    To assess the number of Participants with 100% donor chimerism at 6 months post donor lymphocyte infusion (DLI)


Other Outcome Measures:
  1. To Assess Presence of Gvhd Post Donor Lymphocyte Infusion (DLI) [ Time Frame: 6 months ]
    To assess at 6 months post donor lymphocyte infusion (DLI): GVHD grade & time to resolution

  2. To Determine the Change in Patient-reported Outcomes [ Time Frame: Day 56 post administration of AP1903 ]
    To determine the change in patient-reported outcomes from enrollment to day 56 post administration of AP1903, through the patient quality of life survey.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age >/= 18 years and </= 65 years.
  2. One of the following: a. Acute leukemia past first remission, in first or subsequent relapse, in second or greater remission. Patients in first remission should have with intermediate or high cytogenetic risk factors or flt3 mutation. Patients with relapsed disease. Patients with primary induction failure or relapse are eligible if they have < 10% bone marrow blasts, and no circulating blasts. b. Myelodysplastic syndrome with intermediate or high risk IPSS score, or treatment related MDS. c. CML resistant to tyrosine kinase treatment in a first or subsequent chronic phase or after transformation to accelerated phase or blast crisis.
  3. 2 (continued): d. CLL, Lymphoma or Hodgkin's disease which has failed to achieve remission or recurred following initial chemotherapy. Patients must have at least a PR to salvage therapy, or low bulk untreated relapse (< 2 cm largest mass). e. Multiple myeloma which has relapsed or progressed and has achieved a partial response to salvage chemotherapy.
  4. Patients must have one of the following donor types identified who are willing to donate peripheral blood: a. Related donor, 8/8 HLA-matched for HLA-A, -B, C and DR matched or, b. Matched Unrelated Donor (MUD), 8/8 HLA-matched for HLA A, B, C and DRB1 using allele level typing.
  5. Performance score of at least 80% by Karnofsky.
  6. Adequate major organ system function as demonstrated by: a. Creatinine < 1.8 mg/dl (or creatinine clearance > 40 ml/min) b. Bilirubin < 1.5 mg/dl except for Gilbert's disease c. ALT < 300 IU/ml d. Left ventricular ejection fraction equal or greater than 40%. e. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50% predicted, corrected for hemoglobin.
  7. Patient or patient's legal representative, able to sign informed consent.
  8. Patient or patient's legal representative, parent(s) or guardian able to provide written informed consent for the long-term follow-up gene therapy study 2006-0676.
  9. The patient will need to be available for evaluation within 72 hours of symptoms of GVHD, occurring within 60 days of the planned donor lymphocyte infusion.

Exclusion Criteria:

  1. Uncontrolled active infection.
  2. Positive Beta HCG test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization.
  3. Women of child bearing potential not willing to use an effective contraceptive measure while on study.
  4. Men not willing to use an effective contraception method while on study.
  5. Known sensitivity to any of the products that will be administered during the study.
  6. HIV seropositive.
  7. Prior allogeneic transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01875237


Locations
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United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Bellicum Pharmaceuticals
Investigators
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Principal Investigator: Richard E. Champlin, MD, BS M.D. Anderson Cancer Center
  Study Documents (Full-Text)

Documents provided by M.D. Anderson Cancer Center:

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01875237    
Other Study ID Numbers: 2012-0501
NCI-2013-01666 ( Registry Identifier: NCI CTRP )
First Posted: June 11, 2013    Key Record Dates
Results First Posted: July 16, 2019
Last Update Posted: July 16, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M.D. Anderson Cancer Center:
Leukemia
Myeloma
Myeloproliferative Diseases
Myelodysplastic syndrome
MDS
Lymphoma
Hodgkin disease
Multiple myeloma
MM
Transplant donor
T-cells
G-versus-host disease
GvHD
G-CSF
Filgrastim
Neupogen
Fludarabine
Fludarabine phosphate
Fludara
Melphalan
Alkeran
Alemtuzumab
CAMPATH-1H
Campath
Tacrolimus
Prograf
Mini-methotrexate
AP 1903
Methylprednisolone
Depo-Medrol
Additional relevant MeSH terms:
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Myeloproliferative Disorders
Suicide
Hematologic Diseases
Self-Injurious Behavior
Behavioral Symptoms
Bone Marrow Diseases
Vidarabine
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methotrexate
Fludarabine phosphate
Fludarabine
Melphalan
Alemtuzumab
Tacrolimus
Lenograstim
Prednisolone hemisuccinate
Prednisolone phosphate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents