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A Pilot Study of Safety and Feasibility of Stem Cell Therapy for Aids Lymphoma Using Stem Cells Treated With a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs

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60 Years
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Trial Information

A Pilot Study of Safety and Feasibility of Stem Cell Therapy for Aids Lymphoma Using Stem Cells Treated With a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs


I. To determine the safety and feasibility of using lentivirus-transduced hematopoietic
progenitor cells (HPCs) (lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic
progenitor cells) in the setting of autologous hematopoietic cell transplantation (HCT) for
treatment of AIDS related lymphoma. The safety of the of the genetically modified product
used in the transplant procedure will be assessed by monitoring each subject for adverse
events (procedure related toxicity);, absolute neutrophil count (ANC)/platelet engraftment
(sustained recovery),; and evidence of replication competent vector or vector recombination
with the human immunodeficiency virus (HIV) quasi-species present in the patient.

II. To determine the quantity and duration of vector-marked peripheral blood cells and to
characterize: the duration and level of gene marking and expression of the anti-HIV
ribonucleic acids (RNAs) in these transduced cells, and the characterization of the
integration sites of vector sequences in circulating cells if there is a clinical syndrome
suggestive of a clonal expansion of hematopoietic cells. In addition, the feasibility of the
process will be assessed based on the results of the release testing of the transduced cells
prior to injection into the patient.

III. To determine whether the design of the vector prevents vector mobilization and rescue
by wild-type HIV-1. IV. To measure the effect of HIV infection on the presence of
HIV-resistant blood cells as measured by genetic marking for vector sequences before and
after antiviral treatment interruption.


CONDITIONING: Patients receive carmustine intravenously (IV) over 1-2 hours on days -7 to
-5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2.

TRANSPLANTATION: Patients undergo autologous hematopoietic stem cell transplantation
comprising lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
and non-bound cluster of differentiation (CD)34+ cells IV on day 0. After completion of
study treatment, patients are followed up every 2 weeks for 3 months; at 4, 6, 8, 10, 12,
18, and 24 months; every 6 months for 3 years; and then annually for 10 years.

Inclusion Criteria:

- HIV seropositive at or before the time of lymphoma diagnosis

- Anti-HIV chemotherapy; subjects must be on a multi-drug regimen (excluding
azidothymidine) and have an HIV viral load < 50,000 copies/ml by reverse
transcriptase-polymerase chain reaction (RT-PCR) at the time of study enrollment

- Subjects must agree to have their anti-HIV regimen temporarily stopped, and then all
subjects will stop antiretroviral therapy (ART) for approximately 7 days at the time
they start filgrastim (G-CSF) post-chemotherapy for peripheral blood progenitor cell
(PBPC) mobilization and until the mobilization is complete; in addition, if/when the
CD4 counts return to a level of 450/mm^3 with undetectable HIV levels in blood, the
subjects will undergo an analytic treatment interruption for an indefinite period not
to exceed 6 months

- Karnofsky performance status >= 70%

- Biopsy proven intermediate grade or high-grade non-Hodgkin's lymphoma, including
plasmablastic lymphoma, primary effusion lymphoma, or biopsy-proven Hodgkin's
lymphoma (entities as defined in the World Health Organization [WHO] classification);
tissue histology will be reviewed at the City of Hope; patients with prior marrow
involvement must demonstrate =< 10% involvement pre-stem cell collection

- No psychosocial conditions that would hinder study compliance and follow-up

- Pretreatment serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic
pyruvic transaminase (SGPT) =< 2.5 x institutional upper limit of normal (ULN)

- Serum bilirubin =< 2.5 x institutional ULN

- Patients who are hepatitis C virus (HCV) antibody positive or hepatitis B virus (HBV)
surface antigen positive must be free of clinical evidence of cirrhosis that would
otherwise make them ineligible for HCT, as determined by the Principal Investigator
(PI) in consultation with the Gastrointestinal Service at City of Hope; patients with
HBV and ongoing evidence of viral replication may require therapy prior to receiving
high-dose chemotherapy

- Serum creatinine =< 2 x institutional ULN and a 24 hour urine creatinine clearance >=
60 cc/min

- Prothrombin time (PT)/partial thromboplastin time (PTT) =< 2 x normal

- Forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung for
carbon monoxide (DLCO) >= 50% predicted

- Left ventricular ejection fraction (LVEF) >= 50% (by 2-dimensional [2-D]
echocardiogram or multigated acquisition scan [MUGA]); absence of cardiomyopathy,
congestive heart failure or dysrhythmia

- 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

- HCT Subjects must be on a prophylactic regimen for Pneumocystis carinii pneumonia, or
agree to begin such treatment, if the CD4 counts are =< 200

ELIGIBILITY CRITERIA (HODGKIN LYMPHOMA) - First or greater relapse after initial complete
remission; or partial remission; or induction failure that responds to salvage therapy
with stable disease, partial remission, or complete remission (i.e. chemosensitive


- First complete remission with high risk features as specified by the International
Prognostic Index, or Relapse after prior complete remission; partial remission; or
induction failure that responds to salvage therapy with stable disease, partial remission,
or complete remission (i.e. chemosensitive disease)


- Subjects must complete both the therapeutic and research phases of the G-CSF
mobilization of peripheral blood progenitor cells and

- Subjects must have collected at least 5 x 10^6 CD34+ cells/kg for the research phase
of the collections

Exclusion Criteria:

- Presence of detectible HIV-1 that has C-X-C chemokine receptor type 4 (CXCR4)-tropism

- Any symptomatic bacteria or fungal infection

- AIDS related opportunistic infections within the past year for which treatment has
been unsuccessful would be considered exclusionary but on a case-by-case basis as
determined by the PI

- Active cytomegalovirus (CMV) retinitis or other active CMV-related organ dysfunction;
patients with a history of treated CMV infection are not excluded

- Relapse of Pneumocystis carinii pneumonia within the past year

- Intractable and severe diarrhea, defined as > 1500 cc diarrheal fluid per day, or
diarrhea causing persistent severe electrolyte abnormalities or hypoalbuminemia

- Other AIDS-related syndromes, infectious or otherwise, if perceived to cause
excessive risk for morbidity post-HCT, as determined by the PI

- History of grade III hemorrhagic cystitis due to prior cyclophosphamide chemotherapy

- Pregnant or nursing women

- Any prior malignancy, except those treated with curative intent that are five years
from treatment or cervical and anal squamous cell cancers or superficial basal cell
and squamous cell cancers of skin

- Active central nervous system (CNS) lymphoma; patients with a history of positive
cerebrospinal fluid cytology that has become negative with intrathecal chemotherapy
are eligible

- Abnormal cytogenetics not related to the lymphoma

- History of myocardial infarction or congestive heart failure

- Any 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 medical or physical contraindication or other inability to undergo HPC-apheresis
(HPC-A) collection

- Elevated amylase or lipase SGOT, SGPT > 2.5 x the institutional ULN

- Serum bilirubin > 2.5 x ULN

- Any other laboratory value for complete blood count (CBC) and chemistry panel > 2 x

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety of treatment using the National Cancer Institute (NCI) hematologic Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Outcome Description:

The toxicities observed after each stem cell infusion will be summarized in terms of type (organ affected or laboratory determination such as ANC), severity (by NCI CTCAE version 3 and nadir or maximum values for the laboratory measures), time of onset (i.e., course number), duration, and reversibility of outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.

Outcome Time Frame:

15 years post stem cell infusion

Safety Issue:


Principal Investigator

Amrita Y. Krishnan, MD

Investigator Role:

Study Chair

Investigator Affiliation:

City of Hope Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2007

Completion Date:

Related Keywords:

  • Lymphoma
  • 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 small noncleaved cell lymphoma
  • HIV-associated Hodgkin lymphoma
  • Treatment Experienced
  • Lymphoma
  • Lymphoma, AIDS-Related



City of Hope Medical Center Duarte, California  91010