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

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: NCT01961063
Recruitment Status : Active, not recruiting
First Posted : October 11, 2013
Last Update Posted : February 18, 2022
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
AIDS-related Non-Hodgkin Lymphoma AIDS-related Plasmablastic Lymphoma AIDS-related Primary Effusion Lymphoma HIV Infection Drug: busulfan Biological: lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells Other: pharmacological study Other: laboratory biomarker analysis Phase 1

Detailed Description:


I. To evaluate 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).


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 3 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 31, 2015
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2022

Arm Intervention/treatment
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.
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

Primary Outcome Measures :
  1. Procedure related toxicity as determined by adverse events (AE) grading scale using the Common Terminology Criteria for Adverse Events (CTCAE) version v4.03 [ Time Frame: Up to 5 years ]
    Tables will be created to summarize these toxicities and side effects by dose

  2. Time to Absolute Neutrophil Count (ANC) >= 500/uL [ Time Frame: First 28 days ]
  3. Time to platelet recovery to >= 50,000/uL [ Time Frame: First 90 days ]

Secondary Outcome Measures :
  1. Evidence for and duration of vector-marked PBMC/marrow cells assessed by PCR [ Time Frame: Up to 5 years ]
    PCR-based assay on PBMC

  2. Expression of the RNA transgenes in lineage-specific progeny of the transduced cells assessed by PCR [ Time Frame: Up to 2 years ]
    PCR-based assay on FACS-sorted cells

  3. Effect of ATI on HIV markers and CD4 count [ Time Frame: Up to 5 years ]
    HIV proviral DNA, HIV RNA single copy, and 2-LTR circle DNA from PBMCs

  4. Pharmacokinetic parameters 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 ]
    Cmax, CLsys, Vd, t1/2's, AUC

  5. Ability to obtain suitable numbers of transduced HSPC for engraftment assessed by FACS [ Time Frame: Up to day -2 (Pre-infusion of the investigational drug) ]
    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%.

  6. Feasibility of product manufacturing as evidenced by product release assessed by release assays [ Time Frame: Up to day -2 (Pre-infusion of the investigational drug) ]
    Release assays

Information from the National Library of Medicine

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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

Inclusion Criteria:

  • HIV-1 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); patients who have been in remission for > 1 year post Hodgkin's lymphoma chemotherapy are also considered eligible
  • >= 28 days from completion of frontline chemotherapy for NHL
  • If remission status < 1 year for NHL, 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
  • 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


  • 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 and HCV ribonucleic acid (RNA) 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

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): NCT01961063

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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Sponsors and Collaborators
City of Hope Medical Center
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Principal Investigator: Amrita Krishnan City of Hope Medical Center
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01961063    
Other Study ID Numbers: 13282
NCI-2013-01728 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
13282 ( Other Identifier: City of Hope Medical Center )
First Posted: October 11, 2013    Key Record Dates
Last Update Posted: February 18, 2022
Last Verified: February 2022
Additional relevant MeSH terms:
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Lymphoma, Non-Hodgkin
Plasmablastic Lymphoma
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, Primary Effusion
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Large B-Cell, Diffuse
Lymphoma, B-Cell
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists