Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01961063
First received: September 9, 2013
Last updated: July 11, 2014
Last verified: July 2014

September 9, 2013
July 11, 2014
June 2014
June 2031   (final data collection date for primary outcome measure)
  • Procedure related toxicity as determined by adverse events (AE) grading scale using the Common Terminology Criteria for Adverse Events CTCAE) version v4.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize these toxicities and side effects.
  • Time to Absolute Neutrophil Count (ANC) >= 500/uL [ Time Frame: First 30 days ] [ Designated as safety issue: Yes ]
  • Time to platelet recovery to >= 50,000/uL [ Time Frame: First 90 days ] [ Designated as safety issue: Yes ]
  • Procedure related toxicity as determined by adverse events (AE) grading scale using the Common Terminology Criteria for Adverse Events CTCAE) version v4.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize these toxicities and side effects by dose and by course.
  • Time to Absolute Neutrophil Count (ANC) >= 500/uL [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  • Time to platelet recovery to >= 50,000/uL [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  • Evidence for and duration of vector-marked PBMC/marrow cells [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  • Expression of the RNA transgenes in lineage-specific progeny of the transduced cells [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  • Effect of ATI on HIV markers and CD4 count [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  • Analysis of Compartmental Busulfan Pharmacokinetics [ Time Frame: Day -2 at 0 hours (pre-infusion); 3 hours (just before end of infusion); and at 4, 5, and 6 hours and day -1 at 24 hours ] [ Designated as safety issue: No ]
    Compartmental analyses will be performed using ADAPT II (USC Biomedical Simulations Resource, Los Angeles, CA).
  • Ability to obtain suitable numbers of transduced HSPC for engraftment [ Time Frame: At cell collection completion ] [ Designated as safety issue: No ]
    The number and type of cells will be determined by fluorescence activated cell sorting (FACS) analysis of the final cell product. The minimum target number of CD34+ cells for collection is 7.5 x 10e6 cells/kg and, in the final transduced cell product, the number of CD34+ cells must be >= 2.0 x 10e6 CD34+ cells/kg with total viability > 70%.
  • Analysis of Non-compartmentalBusulfan Pharmacokinetics [ Time Frame: Day -2 at 0 hours (pre-infusion); 3 hours (just before end of infusion); and at 4, 5, and 6 hours and day -1 at 24 hours ] [ Designated as safety issue: No ]
    Non-compartmental analyses will be performed according to the rule of linear trapezoids and statistical moment theory.
  • Analysis of Secondary Pharmacokinetics [ Time Frame: Day -2 at 0 hours (pre-infusion); 3 hours (just before end of infusion); and at 4, 5, and 6 hours and day -1 at 24 hours ] [ Designated as safety issue: No ]
    Secondary pharmacokinetic parameters (Cmax, CLsys, Vd, t1/2's, AUC) will be determined for each individual.
Complete list of historical versions of study NCT01961063 on ClinicalTrials.gov Archive Site
  • Evidence for and duration of vector-marked PBMC/marrow cells [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    PCR-based assay on PBMC
  • Expression of the RNA transgenes in lineage-specific progeny of the transduced cells [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    PCR-based assay on FACS-sorted cells
  • Effect of ATI on HIV markers and CD4 count [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    HIV proviral DNA, HIV RNA single copy, and 2-LTR circle DNA from PBMCs
  • Pharmacokinetics of busulfan [ Time Frame: Day -2 at 0 hours (pre-infusion); 3 hours (just before end of infusion); and at 4, 5, and 6 hours and day -1 at 24 hours ] [ Designated as safety issue: No ]
    Cmax, CLsys, Vd, t1/2's, AUC
  • Ability to obtain suitable numbers of transduced HSPC for engraftment [ Time Frame: Pre-infusion of the investigational drug ] [ Designated as safety issue: No ]
    The number and type of cells will be determined by fluorescence activated cell sorting (FACS) analysis of the final cell product. The minimum target number of CD34+ cells for collection is 7.5 x 10e6 cells/kg and, in the final transduced cell product, the number of CD34+ cells must be >= 2.0 x 10e6 CD34+ cells/kg with total viability >= 70%.
  • Feasibility of product manufacturing as evidenced by product release [ Time Frame: Pre-infusion of the investigational drug ] [ Designated as safety issue: No ]
    Release assays
Not Provided
Not Provided
Not Provided
 
Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
Safety and Feasibility of Gene Transfer After Frontline Chemotherapy for Non-Hodgkin Lymphoma in AIDS Patients Using Peripheral Blood Stem/Progenitor Cells Treated With a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs

This pilot clinical trial studies gene therapy after frontline chemotherapy in treating patients with acquired immune deficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). Placing genes for anti-human immunodeficiency virus (HIV) ribonucleic acid (RNA) into stem/progenitor cells may make the body build an immune response to AIDS. Giving the chemotherapy drug busulfan before gene therapy can help gene-modified cells engraft and work better.

PRIMARY OBJECTIVES:

I. To demonstrate the safety and feasibility of recombinant (r)HIV7-short hairpin RNA targeted to the HIV-1 tat/rev (shI)-trans-active response element (TAR)-chemokine cysteine-cysteine receptor 5 ribozyme (CCR5RZ)-treated hematopoietic stem progenitor cells (HSPC) (lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells) infusion in AIDS patients completing treatment for NHL and non-myeloablative conditioning with busulfan.

II. To demonstrate the engraftment of gene-modified progeny cells following such treatment.

III. To determine if selection of these gene-modified progeny cells occurs during analytical treatment interruption (ATI) of combination anti-retroviral therapy (cART).

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of busulfan in patients with AIDS-related lymphoma (ARL).

II. To determine the effects of HIV-1 infection on the presence of gene-marked peripheral blood mononuclear cells (PBMC) as measured by woodchuck post-transcriptional regulatory element (WPRE) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) performed before, during, and after ATI.

OUTLINE: Patients receive busulfan intravenously (IV) over 3 hours on day -2 followed by lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells IV on day 0.

After completion of study treatment, patients are followed up at 1, 7, 14, and 21 days and 1, 2, 3, 6, 9, 12, 18, and 24 months and then annually for 13 years.

Interventional
Not Provided
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • AIDS-related Diffuse Large Cell Lymphoma
  • AIDS-related Diffuse Mixed Cell Lymphoma
  • AIDS-related Diffuse Small Cleaved Cell Lymphoma
  • AIDS-related Immunoblastic Large Cell Lymphoma
  • AIDS-related Lymphoblastic Lymphoma
  • AIDS-related Small Noncleaved Cell Lymphoma
  • HIV Infection
  • Drug: busulfan
    Given IV
    Other Names:
    • BSF
    • BU
    • Misulfan
    • Mitosan
    • Myeloleukon
  • Biological: lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
    Given IV
    Other Name: lentivirus-transduced hematopoietic progenitor cells
  • Other: pharmacological study
    Correlative studies
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (gene therapy)
Patients receive busulfan IV over 3 hours on day -2 followed by lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells IV on day 0.
Interventions:
  • Drug: busulfan
  • Biological: lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
5
Not Provided
June 2031   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-seropositive at or before the time of lymphoma diagnosis
  • Karnofsky performance status >= 70%
  • Biopsy proven NHL, including plasmablastic lymphoma and primary effusion lymphoma but not T-cell lymphoma; tissue histology will be reviewed at City of Hope (COH)
  • Between 28 days and 3 years from completion of frontline chemotherapy
  • Complete remission documented by computed tomography (CT) or positron emission tomography (PET)-CT scan within 3 months of study entry
  • No diagnosed psychosocial conditions that would hinder study compliance and follow-up
  • Pretreatment serum glutamic oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional upper limit of normal (ULN)
  • Pretreatment serum bilirubin =< 2.5 x institutional ULN or
  • Total bilirubin < 4.5 mg/dl with direct fraction =< 0.3 mg/dl in patients for whom these abnormalities are felt to be due to protease inhibitor therapy
  • Serum creatinine < 2 x the institutional ULN and a 24 hour urine creatinine clearance > 60 cc/min
  • Absence of clinically significant cardiomyopathy, congestive heart failure
  • Cardiac ejection fraction has to be >= 50%
  • Spirometry diffusion capacity (diffusion capacity of the lung for carbon monoxide [DLCO]) >= 50%
  • If the subject is female and of child-bearing potential, subject must have negative serum or urine pregnancy test within 7 days of treatment with research agent; men with partners of child-bearing potential and women of child-bearing potential must be willing to use medically effective birth control methods, e.g. contraceptive pill, condom, or diaphragm and continue this for one year post HSPC infusion
  • Subjects must be on a prophylactic regimen for Pneumocystis carinii pneumonia, or agree to begin such treatment, if the cluster of differentiation (CD)4 counts are < 200 cells/uL

SECONDARY ELIGIBILITY CRITERIA FOR GENE-MODIFIED HSPC INFUSION

  • Subjects must complete the filgrastim (G-CSF)/plerixafor mobilization of peripheral blood progenitor cells and must have collected at least 7.5 x 10^6 CD34+ cells/kg, sufficient for preparation of both, a back-up of 2.5 x 10^6 CD34+ cells and the research product
  • Research product must pass all release tests
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
  • All subjects must have the ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

  • Any AIDS-related opportunistic infection occurring within the past year and for which treatment has been unsuccessful would be considered exclusionary, but this is done on a case-by-case basis as determined by the principal investigator
  • Active cytomegalovirus (CMV) retinitis or other active CMV-related organ dysfunction; patients with a history of treated CMV infection are not excluded
  • Patients who are hepatitis C virus (HCV) antibody positive or hepatitis B virus (HBV) surface antigen positive and HBV DNA positive
  • Pregnant or nursing women
  • Active central nervous system (CNS) lymphoma, history of HIV-associated encephalopathy; dementia of any kind; seizures in the past 12 months; patients with a history of positive cerebrospinal fluid cytology that has become negative with intrathecal chemotherapy and the patient has been in remission for at least 12 months are eligible
  • Any history of HIV-1 associated encephalopathy; dementia of any kind; seizures in the past 12 months; any perceived inability to directly provide informed consent (note: consent may not be obtained by means of a legal guardian)
  • Any medical or physical contraindication or any other inability to undergo HSPC collection
  • Patients should not have any uncontrolled illness including ongoing or active infection
  • Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to G-CSF/filgrastim (Escherichia [E] coli producing cell line), plerixafor or busulfan
  • Patients with other active malignancies other than skin cancers are ineligible for this study
  • Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study will be considered non-compliant
Both
18 Years to 65 Years
No
United States
 
NCT01961063
13282, NCI-2013-01728, 13282
Yes
City of Hope Medical Center
City of Hope Medical Center
National Cancer Institute (NCI)
Principal Investigator: Amrita Krishnan City of Hope Medical Center
City of Hope Medical Center
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP