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Human Immunodeficiency Virus 1 PositivePhase 1NCT02343666

HIV-Resistant Gene Modified Stem Cells and Chemotherapy in Treating Patients With Lymphoma With HIV Infection

A Phase 1 study testing C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs, Carmustine and Filgrastim in people with Human Immunodeficiency Virus 1 Positive and Stage I Adult Hodgkin Lymphoma, run by Fred Hutchinson Cancer Center at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This pilot phase I trial studies the side effects and best dose of human immunodeficiency virus (HIV)-resistant gene modified stem cells in treating HIV-positive patients who are undergoing first-line treatment for Hodgkin or Non-Hodgkin Lymphoma. Read more about this study

Who is it for?
Ages 18 to 66 years
What is being tested?
C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs, Carmustine and Filgrastim
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteUnited States
Study dates
15 Aug 2016to 1 Aug 2020
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 66 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • HIV-1 seropositive
  • Stable, continuous antiretroviral treatment, defined as a multi-drug regimen (excluding zidovudine, also known as azidothymidine [AZT], Retrovir) prior to enrollment, as demonstrated by HIV plasma viral load < 50 copies/mL
  • Previously untreated non-Hodgkin lymphoma or Hodgkin lymphoma; all stages of disease are allowed; also eligible are patients who have started or completed one or more cycles of treatment as part of a planned first line regimen, or those who have received local radiation or surgery or corticosteroids for disease control
  • Planned treatment with standard first line therapy for non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL)
  • Karnofsky performance score >= 70%
  • Subjects must agree to use effective means to prevent conception from enrollment through completion of the study
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  • Female subjects: if of child bearing potential, must have negative serum or urine pregnancy test within 7 days of enrollment
  • Subjects must be on a prophylactic regimen for Pneumocystis jiroveci pneumonia, or agree to begin such treatment, if CD4+ cell counts are observed to be =< 200/ul in peripheral blood
  • Able to understand, and the willingness to give, informed consent for the study

Who cannot join

  • Central nervous system (CNS) lymphoma: CNS involvement by lymphoma, including parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease prior to registration
  • Patients with renal, hepatic, pulmonary, or cardiac disease that exclude delivery of standard chemotherapy
  • Active (uncontrolled) infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents (excluding HIV)
  • Hepatitis B surface antigen positive
  • Hepatitis C virus (HCV) antibody positive and detectable HCV quantitative ribonucleic acid (RNA), with clinical evidence of cirrhosis as determined by the principal investigator
  • Requiring active treatment for Toxoplasma gondii infection
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  • Malignancy other than lymphoma, unless (1) in complete remission and more than 5 years from last treatment, or (2) cervical/anal squamous cell carcinoma in situ or (3) superficial basal cell and squamous cell cancers of the skin
  • History of HIV-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 concurrent or past medical condition that, in the opinion of the investigator, would exclude the subject from participation
  • Patients who have received a vaccine for HIV-1 or any prior gene modified cell product, at any time
  • A medical history of noncompliance with HAART or medical therapy
  • Pregnant women or nursing mothers
  • Use of zidovudine as part of the HAART regimen (a drug substitution for zidovudine at the time of study entry is allowed)
  • Known hypersensitivity to any of the products used in the trial - G-CSF (Neupogen, filgrastim), plerixafor (Mozobil), or any components of the chemotherapeutic agents or O6BG/BCNU in vivo selection regimens

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: A Clinical Trial of Gene-Modified Stem Cells to Generate HIV-Resistant Cells in Conjunction With Standard Chemotherapy for Treatment of Lymphoma in Patients With HIV Infection

This pilot phase I trial studies the side effects and best dose of human immunodeficiency virus (HIV)-resistant gene modified stem cells in treating HIV-positive patients who are undergoing first-line treatment for Hodgkin or Non-Hodgkin Lymphoma. Stem cells are collected from the patient and HIV-resistance genes are placed into the stem cells. The stem cells are then re-infused into the patient. These genetically modified stem cells may help the body make cells that are resistant to HIV infection.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the safety and feasibility of infusing C46/CCR5/P140K lentiviral vector-transduced autologous hematopoietic stem progenitor cells (HSPC) (gene modified, HIV-protected HSPC) after standard first line treatment of lymphoma in patients with HIV infection.

II. To determine the dose of carmustine (BCNU) in combination with O6-benzylguanine (O6BG) that results in selection in vivo of gene-modified HIV resistant cells with minimal toxicity.

III. To estimate the effect of HIV infection on the presence of HIV-resistant blood cells as measured by genetic marking for vector sequences before and after highly active antiretroviral therapy (HAART) interruption.

SECONDARY OBJECTIVES:

  1. Evaluate the molecular and clonal composition of gene-modified cells after standard first line treatment.

II. Evaluate the molecular and clonal composition of gene-modified cells after O6BG/BCNU.

III. Determine the correlation between the level of MGMT(P140K) marking with toxicity and response to O6BG/BCNU chemotherapy.

IV. Characterize the toxicity associated with in vivo selection.

  1. Describe time to disease progression, progression-free survival, treatment-related mortality, time to neutrophil and platelet recovery, and incidence of infections.

TERTIARY OBJECTIVES:

  1. Effect of procedure on the latent HIV reservoir.

II. Effect of procedure on HIV-specific immune reconstitution.

OUTLINE:

MOBILIZATION AND HSPC COLLECTION: Between the second and the last course of planned standard chemotherapy, patients undergo mobilization of peripheral blood stem cells with filgrastim subcutaneously (SC) beginning the day after the last dose of chemotherapy in the previous cycle. If CD34 cell count in peripheral blood at least 24 hours after recovery from nadir is >= 40 CD34 cells/mcL, patients will undergo apheresis collection the next day. If CD34 cell count is < 40 CD34 cells/mcL, plerixafor SC will be administered and patients will undergo apheresis collection the next day. Patients undergo apheresis until a total apheresis product of >= 4.0 x 10^6 CD34+ cells/kg are collected.

STEM CELL INFUSION: Patients receive CD34+ gene-modified C46/CCR5/P140K lentiviral vector-transduced autologous HSPC intravenously (IV) within 2 to 8 days, but no later than 28 days, after completion of the last cycle of first line treatment for lymphoma.

IN VIVO SELECTION WITH O6-BENZYLGUANINE AND CARMUSTINE: Between 28-180 days after infusion of gene-modified HSPC and after hematopoietic recovery from first line treatment, patients with >= 1% and < 10% gene marked cells receive O6-benzylguanine IV over 1 hour, immediately followed by carmustine IV, and followed 7-8 hours later by O6-benzylguanine IV over 1 hour. Treatment continues for an additional course provided that gene marked cells does not meet or exceed 10% of peripheral blood cells and in the absence of unacceptable toxicity.

STRUCTURED TREATMENT INTERRUPTION (STI): Patients achieving >= 10% gene marked cells for 2 consecutive months following infusion of gene-modified HSPC and with CD4+ cell counts and total lymphocyte counts at baseline begin STI of HAART for up to 12 weeks. Patients resume HAART if one of the following criteria occurs: 1) CD4 count < 350 cells/mcL or decline in percent CD4+ cells by > 33% from baseline for three consecutive evaluations; 2) increase in HIV RNA > 100,000 copies/mL on two consecutive evaluations; 3) 12 weeks have passed since discontinuation of HAART; or 4) at the discretion of the infectious disease (ID) consultant or principal investigator (PI).

  • If patient is not on an efavirenz-containing regimen, HAART is discontinued simultaneously. If patient is on an efavirenz-containing regimen, patients will switch from efavirenz to an integrase inhibitor for at least 2 weeks and then discontinue HAART simultaneously.

After completion of study treatment, patients are followed up for 2 years, every 6 months for 3 years and then annually for 15 years.

Being tested
C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs, Carmustine, Filgrastim, Laboratory Biomarker Analysis, O6-Benzylguanine
Medical subject headings
Hodgkin Disease, Lymphoma, Non-Hodgkin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCsBiological

    Given IV

  • CarmustineDrug

    Also called BCNU, Becenum, Becenun, BiCNU

    Given IV

  • FilgrastimBiological

    Also called Filgrastim XM02, Filgrastim-sndz, G-CSF, Granix

    Given SC

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • O6-BenzylguanineDrug

    Also called 6-O-BENZYLGUANINE, O(6)-Benzylguanine

    Given IV

  • PlerixaforDrug

    Also called AMD 3100, JM-3100, Mozobil, SDZ SID 791

    Given SC

Study groups in NCT02343666
Study groupRoleWhat they receive
Treatment (gene modified HPSC)ExperimentalSee Detailed Description.
Receives: Biological: C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs; Drug: Carmustine; Biological: Filgrastim; Other: Laboratory Biomarker Analysis; Drug: O6-Benzylguanine; Drug: Plerixafor

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Feasibility of collection: defined as collection of >= 4.0 x 10^6 CD34+ cells/kg for genetic modification

    Measured: Up to 28 days after completion of last course of first line treatment for lymphoma

  2. Feasibility of infusion of gene modified cells: defined as engraftment of >= 1% gene modified cells

    Engraftment of >= 1% gene modified cells.

    Measured: Up to 28 days after infusion of gene-modified cells to 15 years post-transfusion

  3. Feasibility of O6-benzylguanine/carmustine in vivo selection: defined as selection of gene modified cells to a level >= 10% of peripheral blood cells

    Measured: Up to 180 days after infusion of the gene modified hematopoietic stem progenitor cells

  4. Feasibility of structured treatment interruption: defined as the ability to achieve >= 10% gene modified cell engraftment level and maintain CD4 counts and plasma viremia at levels required for structured treatment interruption eligibility

    Measured: Up to 18 months following infusion of CD34+ gene modified hematopoietic stem progenitor cells

  5. Presence of confirmed replication competent lentivirus

    Any development of confirmed replication competent lentivirus in any patient receiving gene modified cells during the study will be recorded.

    Measured: Up to 15 years

  6. Presence of insertional mutagenesis

    Confirmed insertional mutagenesis in any patient who received gene modified cells during the study

    Measured: Up to 15 years

  7. Safety of infusion of gene modified cells: defined as Common Terminology Criteria for Adverse Events version 4 toxicity >= grade 3 related to the infusion of gene modified cells

    Measured: Up to 30 days after infusion of CD34+ modified hematopoietic stem progenitor cells

  8. Safety of O6-benzylguanine/carmustine in vivo selection, defined as < 25% of patients developing Common Terminology Criteria for Adverse Events version 4 toxicity >= grade 3 associated with O6-benzylguanine/carmustine administration

    Measured: Up to 15 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jan 2015 (estimated)
  2. Study start15 Aug 2016
  3. Primary completion1 Aug 2020 (estimated)

Why it stopped: Administrative closure prior to any enrollments

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02343666
Sponsor's protocol ID
2673.00
Other IDs
NCI-2014-02395, 2673, 2673.00, P30CA015704, R01HL116217
Status last verified
Nov 2018
First submitted
30 Dec 2014
Last updated
20 Nov 2018
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs, Carmustine and Filgrastim in people with Human Immunodeficiency Virus 1 Positive and Stage I Adult Hodgkin Lymphoma, run by Fred Hutchinson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 20 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Feasibility of collection: defined as collection of >= 4.0 x 10^6 CD34+ cells/kg for genetic modification (time frame: Up to 28 days after completion of last course of first line treatment for lymphoma). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02343666.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2018.

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