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

NCT01875237 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2012-0501NCI-2013-01666
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukemia; Myeloma; Myeloproliferative Diseases

Keywords

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; Medrol; Solu-Medrol; Stem cell infusion; Donor lymphocyte infusion; DLI; Questionnaire; Survey

Outcome Measures

Primary Outcomes (1)

• To Evaluate the Safety of Donor Lymphocyte Infusion Followed by Dimerizer Drug, AP1903 by Number of Participants With Adverse Events.

  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.

  up to 3.5 years

Secondary Outcomes (7)

• Number of Participants Assessed Post Donor Lymphocyte Infusion (DLI): Disease-free Survival & Non-relapse Mortality, Chimerism and GVHD.

  6 months

• To Assess the Incidence of Epstein-Barr Virus -PTLD or EBV Reactivation Requiring Therapy Post DLI.

  1 year

• To Assess the Proportion of Patients Developing Grade I-IV Acute GvHD

  Day 28, 56, and 180 post DLI.

• To Assess the Proportions of GvHD Response Post-administration of AP1903.

  Day 3, 7, 14, 28, and 56 post-administration of AP1903

• To Assess the Incidence of GvHD Treatment Failure Post-administration of AP1903.

  Day 3, 7, 14, 28, and 56 post-administration of AP1903.

Other Outcomes (2)

• To Assess Presence of Gvhd Post Donor Lymphocyte Infusion (DLI)

  6 months

• To Determine the Change in Patient-reported Outcomes

  Day 56 post administration of AP1903

Study Arms (1)

Stem Cell Transplant + Modified T-Cells + Chemotherapy

EXPERIMENTAL

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; 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

Interventions

Fludarabine DRUG

40 mg/m2 by vein on Days -6 to -3.

Also known as: Fludarabine phosphate, Fludara

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Melphalan DRUG

140 mg/m2 by vein on Day -2.

Also known as: Alkeran

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Alemtuzumab DRUG

50 mg by vein on Day -1.

Also known as: CAMPATH-1H, Campath

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Stem Cell infusion PROCEDURE

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).

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Tacrolimus DRUG

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.

Also known as: Prograf

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Mini Methotrexate DRUG

5 mg/m2 by vein on Days +1, +3, +6.

Stem Cell Transplant + Modified T-Cells + Chemotherapy

G-CSF DRUG

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.

Also known as: Filgrastim, Neupogen

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Donor Lymphocyte Infusion (DLI) PROCEDURE

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.

Stem Cell Transplant + Modified T-Cells + Chemotherapy

AP1903 DRUG

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.

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Methylprednisolone DRUG

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.

Also known as: Depo-Medrol, Medrol, Solu-Medrol

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Questionnaire BEHAVIORAL

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.

Also known as: Survey

Stem Cell Transplant + Modified T-Cells + Chemotherapy

Eligibility Criteria

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

You may qualify if:

• Age \>/= 18 years and \</= 65 years.
• 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.
• (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.
• 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.
• Performance score of at least 80% by Karnofsky.
• 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.
• Patient or patient's legal representative, able to sign informed consent.
• 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.
• 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.

You may not qualify if:

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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Bellicum Pharmaceuticals: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia; Neoplasms, Plasma Cell; Myelodysplastic Syndromes; Lymphoma; Hodgkin Disease; Multiple Myeloma

Interventions

fludarabine; fludarabine phosphate; Melphalan; Alemtuzumab; Tacrolimus; Granulocyte Colony-Stimulating Factor; Filgrastim; AP 1903 reagent; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Surveys and Questionnaires

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Results Point of Contact

• Title: Champlin,Richard,M.D. / Stem Cell Transplantation
• Organization: UT MD Anderson Cancer Center

rchampli@mdanderson.org

713-792-8750

Study Officials

• Richard E. Champlin, MD, BS

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2013
• First Posted: June 11, 2013
• Study Start: December 27, 2013
• Primary Completion: March 7, 2017
• Study Completion: March 7, 2017
• Last Updated: July 16, 2019
• Results First Posted: July 16, 2019

Record last verified: 2019-06

Locations

US (1)