Gene Therapy-Treated Stem Cells in Treating Patients Undergoing Stem Cell Transplant for Intermediate-Grade or High-Grade AIDS-Related Lymphoma

NCT00569985 | Completed Phase 1 DMC

• 3 other identifiers: 04047CHNMC-04047NCI-2012-00437
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This pilot clinical trial studies biological therapy in treating patients with acquired immune deficiency syndrome (AIDS)-related lymphoma undergoing stem cell transplant. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving biological therapy as part of the stem cell transplant may be more effective in treating patients with AIDS-related lymphoma

Conditions

Lymphoma

Keywords

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

Outcome Measures

Primary Outcomes (6)

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

  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.

  15 years post stem cell infusion

• Survival of shI-TAR-CCR5RZ-marked cells in the peripheral blood, demonstrated by presence of transgene by Q-PCR using primers specific for rHIV7-shI-TAR-CCR5RZ in serial samples of peripheral blood

  24 months post stem cell infusion

• Determination of RNA transgene expression in samples of peripheral blood mononuclear cells (PBMCs) or marrow before and after infusion, analyzed by Northern blotting/hybridization

  For detection of the shRNA, we will use a quantitative real-time PCR assay.

  Day 1 post stem cell infusion

• Analysis of vector rescue by HIV

  Integration analysis will be performed only if there is a clinical syndrome that suggests clonal expansion of hematopoietic cells. In that situation, the method of insertion site location will use a linear amplification mediated (LAM)-PCR technique. If positive vector sequences are found in the plasma, confirmation of vector rescue will be done by isolation of HIV and subsequent HIV sequencing.

  15 years post stem cell infusion

• Ability to obtain suitable numbers of lentiviral vector treated HPC-A

  The number and type of cells will be determined by fluorescence-activated cell sorting (FACS) analysis of the final cell product. Target number for untransduced cells in the final therapeutic cell product is 2.5 x 10\^6 CD34+ cells/kg. Minimum target number of CD34+ cells for transduction is 5 x 10\^6/kg and in the final transduced cell product, the number of CD34+ cells must be \>= 2.0 x 10\^6 CD34+ cells/kg with total viability \>= 70%. The relative or absolute number of transduced CD34+ cells will be determined.

  Day 2 post apheresis

• Determination of replication competent lentivirus (RCL) and HIV-1/vector recombination

  15 years post stem cell infusion

Study Arms (1)

Treatment (autologous HCT)

EXPERIMENTAL

CONDITIONING: Patients receive carmustine 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 CD34+ cells IV on day 0.

Biological: lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells; Drug: carmustine; Drug: cyclophosphamide; Drug: etoposide; Procedure: autologous hematopoietic stem cell transplantation

Interventions

lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells BIOLOGICAL

Undergo autologous hematopoietic stem cell transplantation comprising lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells and non-bound CD34+ cells

Also known as: lentivirus-transduced hematopoietic progenitor cells

Treatment (autologous HCT)

carmustine DRUG

Given IV

Also known as: BCNU, BiCNU, bis-chloronitrosourea

Treatment (autologous HCT)

cyclophosphamide DRUG

Given IV

Also known as: CPM, CTX, Cytoxan, Endoxan, Endoxana

Treatment (autologous HCT)

etoposide DRUG

Given IV

Also known as: EPEG, VP-16, VP-16-213

Treatment (autologous HCT)

autologous hematopoietic stem cell transplantation PROCEDURE

Undergo autologous hematopoietic stem cell transplantation comprising lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells and non-bound CD34+ cells

Treatment (autologous HCT)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• Presence of detectible HIV-1 that has C-X-C chemokine receptor type 4 (CXCR4)-tropism
• Any symptomatic bacteria or fungal infection
• 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

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010-3000, United States

Location

MeSH Terms

Conditions

Lymphoma

Interventions

Carmustine; Cyclophosphamide; Etoposide

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Amrita Y. Krishnan, MD

  City of Hope Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2007
• First Posted: December 10, 2007
• Study Start: June 1, 2007
• Primary Completion: November 12, 2019
• Study Completion: November 12, 2019
• Last Updated: November 15, 2019

Record last verified: 2019-11

Locations

US (1)