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Genetically Modified Peripheral Blood Stem Cell Transplant in Treating Patients With HIV-Associated Non-Hodgkin or Hodgkin Lymphoma

Primary Purpose

Adult Nasal Type Extranodal NK/T-cell Lymphoma, AIDS-related Diffuse Large Cell Lymphoma, AIDS-related Diffuse Mixed Cell Lymphoma

Status

Withdrawn

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

carmustine

cytarabine

melphalan

etoposide

O6-benzylguanine

autologous hematopoietic stem cell transplantation

peripheral blood stem cell transplantation

laboratory biomarker analysis

About this trial

This is an interventional treatment trial for Adult Nasal Type Extranodal NK/T-cell Lymphoma

Eligibility Criteria

18 Years - 66 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

HIV seropositive
Antiretroviral treatment for at least one month, defined as a multi-drug regimen (excluding azacitidine [AZT])
HIV plasma viral load has decreased by 1.5 logs or viral load < 5000 copies/ml
Non-Hodgkin or Hodgkin lymphoma without active central nervous system (CNS) involvement associated with poor prognosis with medical therapy alone or for which autologous peripheral blood stem cell (PBSC) transplant is indicated:
- Hodgkin's lymphoma beyond first remission; first partial remission; induction failure with subsequent response to salvage therapy
- Non-Hodgkin's Lymphoma beyond first remission: first partial remission; induction failure with subsequent response to salvage therapy
- Chemotherapy responsive disease
Karnofsky performance score >= 70%
Subjects must agree to use effective contraception from enrollment through completion of the study
Female subjects: if of child bearing potential, must have negative serum or urine pregnancy test within 7 days of treatment
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
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

Serum creatinine > 2 times upper limit of normal
Serum bilirubin greater than 3 times the upper limits of normal, unless determined to be a result of the primary hematologic malignancy or attributed to Gilbert's syndrome
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limits of normal, unless determined to be a result of the primary hematologic malignancy or attributed to Gilbert's syndrome
Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung of carbon monoxide (DLCO) parameters < 60% predicted (corrected for hemoglobin)
Left ventricular ejection fraction (LVEF) < 50% or coronary artery disease requiring treatment
Active infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents (excluding HIV)
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 (P.I.) in consultation with the Gastrointestinal Service; patients with HBV and ongoing evidence of viral replication may require therapy prior to receiving high-dose chemotherapy
Positive serology for Toxoplasma gondii AND requiring treatment or with evidence of active infection
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)
A medical history of noncompliance with highly active anti-retroviral therapy (HAART) or medical therapy

Sites / Locations

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (gene modified peripheral blood cell transplant)

Arm Description

CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0. Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.

Outcomes

Primary Outcome Measures

Safety of infusion of gene-modified cells, measured by grade 3 or greater toxicities related to infusion of gene-modified cells using the Common Toxicity Criteria version 4.0(CTCv.4)

Safety of O6BG/BCNU in vivo selection, defined as less than 25% of patients developing grade 3 or greater non-hematopoietic toxicity or grade 4 CTCv.4 hematopoietic toxicity

Safety of structured treatment interruption defined as no decline in CD4 count by more than 25%, no HIV RNA more than 10,000 copies/mL; and no elevation of immune activation markers

Efficacy of gene transduction, defined as collection of more than 4.5 x 10^6 CD34+ cells/kg cells for genetic modification and evidence of gene-marked cells before HSC infusion

Efficacy of infusion of gene-modified cells, defined as engraftment of at least1% gene-modified cells

Efficacy of O6BG/BCNU in vivo selection, defined as selection of gene-modified cells to a level at least 10% of peripheral blood cells

Secondary Outcome Measures

Full Information

NCT ID

NCT01769911

First Posted

January 15, 2013

Last Updated

May 6, 2015

Sponsor

Fred Hutchinson Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01769911

Brief Title

Genetically Modified Peripheral Blood Stem Cell Transplant in Treating Patients With HIV-Associated Non-Hodgkin or Hodgkin Lymphoma

Official Title

AUTOLOGOUS TRANSPLANTATION AND STEM CELL BASED-GENE THERAPY FOR THE TREATMENT OF HIV-ASSOCIATED LYMPHOMA

Study Type

Interventional

2. Study Status

Record Verification Date

May 2015

Overall Recruitment Status

Withdrawn

Study Start Date

February 2015 (undefined)

Primary Completion Date

February 2019 (Anticipated)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Fred Hutchinson Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This clinical trial studies genetically modified peripheral blood stem cell transplant in treating patients with HIV-associated non-Hodgkin or Hodgkin lymphoma. Giving chemotherapy before a peripheral 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. More chemotherapy or radiation therapy is then given to prepare the bone marrow for the stem cell transplant. Laboratory-treated stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and radiation therapy

Detailed Description

PRIMARY OBJECTIVES: I. To determine the safety and feasibility of infusing gene-modified, human immunodeficiency virus (HIV)-protected hematopoietic stem cells (HSC) after high-dose chemotherapy for treatment of acquired immunodeficiency syndrome (AIDS)-related lymphoma. II. To determine the dose of carmustine (BCNU) in combination with O^6-benzylguanine (O6BG) that results in selection in vivo of gene-modified HIV-resistant cells. 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 antiviral treatment interruption. SECONDARY OBJECTIVES: I. Evaluate the molecular and clonal composition of gene-modified cells after hematopoietic cell transplant (HCT). II. Evaluate the molecular and clonal composition of gene-modified cells after O6BG/BCNU. III. Determine the correlation of the level of O6-methylguanine- methyltransferase (MGMT) (P140K) marking with toxicity and response. IV. Characterize the toxicity associated with in vivo selection. V. Determine the efficacy of the procedure for treatment of lymphoma: defined as time to disease progression, progression-free survival, treatment-related mortality, time to neutrophil and platelet recovery, and incidence of infections. TERTIARY OBJECTIVES: I. Effect of procedure on the latent HIV reservoir. II. Effect of procedure on HIV-specific immune reconstitution. OUTLINE: CONDITIONING: Patients receive carmustine intravenously (IV) over 3 hours on day -7, cytarabine IV over 2 hours twice daily (BID) and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0. Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection. After completion of study treatment, patients are followed up periodically for 15 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Adult Nasal Type Extranodal NK/T-cell 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 Lymphoblastic Lymphoma, AIDS-related Peripheral/Systemic Lymphoma, AIDS-related Small Noncleaved Cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, HIV-associated Hodgkin Lymphoma, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncutaneous Extranodal Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Hairy Cell Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage I AIDS-related Lymphoma, Stage II AIDS-related Lymphoma, Stage III AIDS-related Lymphoma, Stage IV AIDS-related Lymphoma, T-cell Large Granular Lymphocyte Leukemia, Testicular Lymphoma, Waldenström Macroglobulinemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (gene modified peripheral blood cell transplant)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

carmustine

Other Intervention Name(s)

BCNU, BiCNU, bis-chloronitrosourea

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

cytarabine

Other Intervention Name(s)

ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

melphalan

Other Intervention Name(s)

Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

etoposide

Other Intervention Name(s)

EPEG, VP-16, VP-16-213

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

O6-benzylguanine

Other Intervention Name(s)

Intervention Description

Given IV

Intervention Type

Procedure

Intervention Name(s)

autologous hematopoietic stem cell transplantation

Intervention Description

Undergo transduced and/or non-transduced transplant

Intervention Type

Procedure

Intervention Name(s)

peripheral blood stem cell transplantation

Other Intervention Name(s)

PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

Intervention Description

Undergo transduced and/or non-transduced transplant

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Safety of infusion of gene-modified cells, measured by grade 3 or greater toxicities related to infusion of gene-modified cells using the Common Toxicity Criteria version 4.0(CTCv.4)

Time Frame

Up to day 180

Title

Safety of O6BG/BCNU in vivo selection, defined as less than 25% of patients developing grade 3 or greater non-hematopoietic toxicity or grade 4 CTCv.4 hematopoietic toxicity

Time Frame

Up to day 180

Title

Safety of structured treatment interruption defined as no decline in CD4 count by more than 25%, no HIV RNA more than 10,000 copies/mL; and no elevation of immune activation markers

Time Frame

During the 12 weeks without HAART

Title

Efficacy of gene transduction, defined as collection of more than 4.5 x 10^6 CD34+ cells/kg cells for genetic modification and evidence of gene-marked cells before HSC infusion

Time Frame

Up to 3 months

Title

Efficacy of infusion of gene-modified cells, defined as engraftment of at least1% gene-modified cells

Time Frame

Up to 3 months

Title

Efficacy of O6BG/BCNU in vivo selection, defined as selection of gene-modified cells to a level at least 10% of peripheral blood cells

Time Frame

Up to 3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

66 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: HIV seropositive Antiretroviral treatment for at least one month, defined as a multi-drug regimen (excluding azacitidine [AZT]) HIV plasma viral load has decreased by 1.5 logs or viral load < 5000 copies/ml Non-Hodgkin or Hodgkin lymphoma without active central nervous system (CNS) involvement associated with poor prognosis with medical therapy alone or for which autologous peripheral blood stem cell (PBSC) transplant is indicated: Hodgkin's lymphoma beyond first remission; first partial remission; induction failure with subsequent response to salvage therapy Non-Hodgkin's Lymphoma beyond first remission: first partial remission; induction failure with subsequent response to salvage therapy Chemotherapy responsive disease Karnofsky performance score >= 70% Subjects must agree to use effective contraception from enrollment through completion of the study Female subjects: if of child bearing potential, must have negative serum or urine pregnancy test within 7 days of treatment 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 Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Serum creatinine > 2 times upper limit of normal Serum bilirubin greater than 3 times the upper limits of normal, unless determined to be a result of the primary hematologic malignancy or attributed to Gilbert's syndrome Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limits of normal, unless determined to be a result of the primary hematologic malignancy or attributed to Gilbert's syndrome Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung of carbon monoxide (DLCO) parameters < 60% predicted (corrected for hemoglobin) Left ventricular ejection fraction (LVEF) < 50% or coronary artery disease requiring treatment Active infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents (excluding HIV) 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 (P.I.) in consultation with the Gastrointestinal Service; patients with HBV and ongoing evidence of viral replication may require therapy prior to receiving high-dose chemotherapy Positive serology for Toxoplasma gondii AND requiring treatment or with evidence of active infection 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) A medical history of noncompliance with highly active anti-retroviral therapy (HAART) or medical therapy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ann Woolfrey

Organizational Affiliation

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Official's Role

Principal Investigator

Facility Information:

Facility Name

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

City

Seattle

State/Province

Washington

ZIP/Postal Code

98109

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Genetically Modified Peripheral Blood Stem Cell Transplant in Treating Patients With HIV-Associated Non-Hodgkin or Hodgkin Lymphoma

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