Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
Primary Purpose
AIDS-related Non-Hodgkin Lymphoma, AIDS-related Plasmablastic Lymphoma, AIDS-related Primary Effusion Lymphoma
Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
busulfan
lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
pharmacological study
laboratory biomarker analysis
Sponsored by
About this trial
This is an interventional treatment trial for AIDS-related Non-Hodgkin Lymphoma
Eligibility Criteria
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
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 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
Sites / Locations
- City of Hope Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (gene therapy)
Arm Description
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.
Outcomes
Primary Outcome Measures
Procedure related toxicity as determined by adverse events (AE) grading scale using the Common Terminology Criteria for Adverse Events (CTCAE) version v4.03
Tables will be created to summarize these toxicities and side effects by dose
Time to Absolute Neutrophil Count (ANC) >= 500/uL
Time to platelet recovery to >= 50,000/uL
Secondary Outcome Measures
Evidence for and duration of vector-marked PBMC/marrow cells assessed by PCR
PCR-based assay on PBMC
Expression of the RNA transgenes in lineage-specific progeny of the transduced cells assessed by PCR
PCR-based assay on FACS-sorted cells
Effect of ATI on HIV markers and CD4 count
HIV proviral DNA, HIV RNA single copy, and 2-LTR circle DNA from PBMCs
Pharmacokinetic parameters of busulfan
Cmax, CLsys, Vd, t1/2's, AUC
Ability to obtain suitable numbers of transduced HSPC for engraftment assessed by FACS
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 assessed by release assays
Release assays
Full Information
NCT ID
NCT01961063
First Posted
September 9, 2013
Last Updated
February 19, 2023
Sponsor
City of Hope Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT01961063
Brief Title
Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 31, 2015 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
December 30, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
Detailed Description
PRIMARY OBJECTIVES:
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).
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 3 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
AIDS-related Non-Hodgkin Lymphoma, AIDS-related Plasmablastic Lymphoma, AIDS-related Primary Effusion Lymphoma, HIV Infection
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (gene therapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
BSF, BU, Misulfan, Mitosan, Myeloleukon
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
Other Intervention Name(s)
lentivirus-transduced hematopoietic progenitor cells
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
pharmacological study
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Procedure related toxicity as determined by adverse events (AE) grading scale using the Common Terminology Criteria for Adverse Events (CTCAE) version v4.03
Description
Tables will be created to summarize these toxicities and side effects by dose
Time Frame
Up to 5 years
Title
Time to Absolute Neutrophil Count (ANC) >= 500/uL
Time Frame
First 28 days
Title
Time to platelet recovery to >= 50,000/uL
Time Frame
First 90 days
Secondary Outcome Measure Information:
Title
Evidence for and duration of vector-marked PBMC/marrow cells assessed by PCR
Description
PCR-based assay on PBMC
Time Frame
Up to 5 years
Title
Expression of the RNA transgenes in lineage-specific progeny of the transduced cells assessed by PCR
Description
PCR-based assay on FACS-sorted cells
Time Frame
Up to 2 years
Title
Effect of ATI on HIV markers and CD4 count
Description
HIV proviral DNA, HIV RNA single copy, and 2-LTR circle DNA from PBMCs
Time Frame
Up to 5 years
Title
Pharmacokinetic parameters of busulfan
Description
Cmax, CLsys, Vd, t1/2's, AUC
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
Title
Ability to obtain suitable numbers of transduced HSPC for engraftment assessed by FACS
Description
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%.
Time Frame
Up to day -2 (Pre-infusion of the investigational drug)
Title
Feasibility of product manufacturing as evidenced by product release assessed by release assays
Description
Release assays
Time Frame
Up to day -2 (Pre-infusion of the investigational drug)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amrita Krishnan
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
We'll reach out to this number within 24 hrs