PRIMARY OBJECTIVES:
I. Safety, defined as timely engraftment (the collective establishment of a persistent
absolute neutrophil count of at least 500 cells/mm^3 and platelet count of 20,000 cells/mm^3
without transfusion for 3 consecutive days) at one month post transplant, in the absence of
any study candidate specific grade 3 and 4 non-hematopoietic organ toxicity or any clonal
expansion.
II. Efficacy of the candidate product, defined as establishment of > 5% mononuclear blood
cells expressing anti-HIV genes in the peripheral blood at 3 months post-transplant.
SECONDARY OBJECTIVES:
I. To determine the presence, quantity, and duration of gene modified HIV-1 resistant
peripheral blood cells and gut mucosal immune cells.
II. To study the integration sites of vector sequences in circulating cells. III. To study
progression-free survival. IV. To study overall survival. V. To study complete response rate
and duration. VI. To study partial response rate and duration. VII. To study time to
neutrophil engraftment (first of 3 consecutive days of absolute neutrophil count [ANC] > 500
cells/mm^3).
VIII. To study time to platelet engraftment (first of 3 consecutive days of platelets >
20,000 cells/mm^3 without platelet transfusions 7 days prior).
IX. To study hematologic function at day 100 (ANC > 1500, hemoglobin [Hb] > 10 g/dl without
transfusion and platelets > 100,000) X. To study cluster of differentiation (CD)4 recovery at
the conclusion of the trial.
XI. To study safety in terms of toxicities, infections, transfusions, and infusion-related
reactions.
XII. To study HIV-1 viral load over time. XIII. To study persistence of vector-transduced
cells over time.
TERTIARY OBJECTIVES:
I. To evaluate the presence and the magnitude of expansion of HIV-1 resistant immune cells in
the peripheral blood and gut mucosa of transplanted participants, subsequent to withholding
anti-retroviral therapy (ART).
OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.
Patients receive BEAM regimen administered as standard of care comprising carmustine on day
-6, cytarabine twice daily (BID) on days -5 to -2, etoposide BID on days -5 to -2, and
melphalan on day -1. Patients undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR
decoy-transduced autologous CD34-positive hematopoietic progenitor cells over 1 hour.
After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 42, 60,
90, 120, 180, 240, 300, 360, 420, 480, 520, 600, 660, and 720, and then yearly for at least
15 years.
Inclusion Criteria:
- Inclusion criteria associated with type and status of lymphoma
- Biopsy-proven intermediate or high-grade non-Hodgkin's lymphoma, meeting one of the
following criteria (timeline 4 months prior to start of trial):
- In partial remission
- Relapsed after initial complete remission
- Failed induction therapy, but responds to salvage therapy (i.e., chemosensitive
disease)
- In complete remission with high-risk features as specified by the International
Prognostic Index
- Biopsy-proven advanced stage follicular lymphoma, that have failed at least two lines
of therapy multi-agent chemotherapy, but responds to salvage therapy (i.e.,
chemosensitive disease) (timeline 4 months prior to start of trial)
- Biopsy-proven advanced stage mantle cell lymphoma with proliferation-related Ki-67
antigen (Ki-67) > 10% in first complete remission (timeline 4 months prior to start of
trial)
- Biopsy-proven Hodgkin's lymphoma, meeting one of the following criteria (timeline 4
months prior to start of trial)
- In first, or greater relapse after initial complete remission
- In partial remission
- Failed induction therapy, but responds to salvage therapy (i.e., chemosensitive
disease)
- Biopsy-proven Burkitt's lymphoma, meeting one of the following criteria (timeline 4
months prior to start of trial):
- In second complete remission after relapse following initial complete remission,
- Failed induction therapy, but responds (very good partial remission, complete
remission, or near complete remission) to salvage therapy (i.e., chemosensitive
disease)
- Biopsy proven plasmablastic lymphomas, or peripheral T cell lymphoma (with the
exception of anaplastic lymphoma kinase positive [ALK+] type in first or second
complete remission) (timeline 4 months prior to start of trial)
- INCLUSION CRITERIA ASSOCIATED WITH HIV-1 STATUS
- HIV-1 infection, as documented by any federally approved, licensed HIV rapid test
performed in conjunction with screening (or enzyme linked immunosorbent assay [ELISA],
test kit, and confirmed by western blot or other approved test); alternatively, this
documentation may include a record demonstrating that another physician has documented
the participant's HIV status based on either: 1) approved diagnostic tests, or 2) the
referring physician's written record that HIV infection was documented, with
supporting information on the participant's relevant medical history and/or current
management of HIV infection
- Must be on a multi-drug anti-HIV regimen (excluding zidovudine [AZT, ZDV, Retrovir®,
or agents containing zidovudine (e.g., Combivir® and Trizivir®)], and efavirenz
[Sustiva®, or agents containing efavirenz (e.g., Atripla®)]), and have an HIV-1 viral
load < 50 copies/mL by reverse transcriptase-polymerase chain reaction (RT-PCR) at the
time of study enrollment; participants on zidovudine [AZT, ZDV, Retrovir®; including
Combivir® and Trizivir®] and efavirenz [Sustiva®; including Atripla®] must switch to
an alternative regimen without anticipated drug-drug interactions or myelosuppressive
properties based on known viral resistance patterns and/or ART history, such as
raltegravir and Truvada (emtricitabine and tenofovir) at least two weeks prior to the
transplant
- Participants with CD4 counts > 50/microL are eligible for this study if their viral
load is < 50 copies/mL by reverse transcription polymerase chain reaction (RT-PCR)
since majority of the participants have received aggressive chemotherapy that can
potentially decrease the CD4 counts despite the ART therapy; timeline: within 3 weeks
prior to start of trial
- GENERAL INCLUSION CRITERIA (TIMELINE: 8 WEEKS PRIOR TO START OF TRIAL, UNLESS
OTHERWISE SPECIFIED)
- Karnofsky performance status of 70-100%; Eastern Cooperative Oncology Group (ECOG)
performance status =< [2]
- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) >= 2.5 times upper limit of normal (ULN)
- Serum bilirubin =< 2.5 times ULN except for participants who are on atazanavir or
indinavir, provided that the participant's direct bilirubin is within normal
institutional limits
- Participants who are hepatitis C virus antibody positive, or hepatitis B virus surface
antigen positive must be free of clinical evidence of cirrhosis as determined by the
principal investigator in consultation with the gastroenterology service; timeline:
within 3 weeks prior to start of trial
- Participants with hepatitis B should be on appropriate anti-viral therapy at the time
of the transplant, and their viral load should be under control; timeline: within 3
weeks prior to start of trial
- Serum creatinine =< 2 times ULN; timeline: within 3 weeks prior to start of trial
- Creatinine clearance >= 60 mL/min; timeline: within 3 weeks prior to start of trial
- Prothrombin time (PT)/partial thromboplastin time (PTT) =< 2 times normal; timeline:
within 3 weeks prior to start of trial
- Forced expiratory volume in 1 second (FEV-1) or diffusion capacity of the lung for
carbon monoxide (DLCO) >= 50% predicted; timeline: within 4 weeks prior to start of
trial
- Left ventricular ejection fraction (LVEF) >= 50% by 20-dimensional (20D)
echocardiogram (ECHO) or multigated acquisition (MUGA) scan; timeline: within 4 weeks
prior to start of trial
- Not pregnant or nursing, with negative pregnancy test; timeline: within 3 weeks prior
to start of trial
- Life expectancy of greater than 3 months
- Ability to understand and the willingness to sign a written informed consent document
- Receipt of a stable ART regimen for at least 3 weeks prior to start of trial
Exclusion Criteria:
- Participants with > 5% involvement of bone marrow by malignant cells (either by manual
count or flow cytometry) prior to stem cell collection
- Participants with any abnormal cytogenetics in the bone marrow not related to the
lymphoma, and not deemed to be constitutional
- Participants with unexplained anemia, and/or thrombocytopenia
- Participants with clear evidence of myeloproliferative disorders, or myelodysplastic
disorders in the marrow
- Presence of any active central nervous system (CNS) disease at the time of evaluation
(parenchymal or leptomeningeal)
- Any history of HIV-1 associated encephalopathy
- History of other acquired immune deficiency syndrome (AIDS)-related syndromes that are
perceived to cause excessive risk for morbidity post-transplantation, as determined by
the principal investigator
- Symptomatic/active bacterial, or fungal, or any other opportunistic infection
- Active cytomegalovirus (CMV) retinitis, or other active CMV-related organ dysfunction
- Relapse of pneumocystis carinii pneumonia within the past year
- Intractable, severe diarrhea, defined as > 1.500 cc diarrheal fluid per day, or
diarrhea causing persistent severe electrolyte abnormalities, or hypoalbuminemia
- History of active myocardial ischemia, cardiomyopathy, uncontrolled dysrhythmia, or
congestive heart failure within the last 6 months before the evaluation
- Dementia of any kind
- Seizures within the past 12 months
- History of grade III hemorrhagic cystitis due to prior cyclophosphamide chemotherapy
- History of other prior malignancy, except squamous cell carcinoma of the cervix or
anus, superficial basal cell or squamous cell skin cancer, or other malignancy
curatively treated more than 5 years ago
- Active psychosocial condition that would hinder study compliance and follow-up
- Any perceived inability to directly (and without the means of a legal guardian)
provide informed consent
- Any medical or physical contraindication, or other inability to undergo hematopoietic
progenitor cell (HPC) collection
- Participants who are receiving any other investigational agents
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study; breastfeeding should be discontinued;
these potential risks may also apply to other agents used in this study
