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Report for Clinical Trial NCT02343666

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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.

NCT02343666 Human Immunodeficiency Virus 1 Positive Stage I Adult Hodgkin Lymphoma Stage I Adult Non-Hodgkin Lymphoma Stage II Adult Hodgkin Lymphoma Stage II Adult Non-Hodgkin Lymphoma Stage III Adult Hodgkin Lymphoma Stage III Adult Non-Hodgkin Lymphoma Stage IV Adult Hodgkin Lymphoma Stage IV Adult Non-Hodgkin Lymphoma
MeSH: HIV Infections Acquired Immunodeficiency Syndrome Lymphoma Lymphoma, Non-Hodgkin Hodgkin Disease
HPO: Hodgkin lymphoma Lymphoma Non-Hodgkin lymphoma

6 Interventions

Name: C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs

Description: Given IV

Type: Biological

Treatment (gene modified HPSC)

Name: Carmustine

Description: Given IV

Type: Drug

Treatment (gene modified HPSC)

Name: Filgrastim

Description: Given SC

Type: Biological

Treatment (gene modified HPSC)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Treatment (gene modified HPSC)

Name: O6-Benzylguanine

Description: Given IV

Type: Drug

Treatment (gene modified HPSC)

Name: Plerixafor

Description: Given SC

Type: Drug

Treatment (gene modified HPSC)


Primary Outcomes

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

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

Description: Engraftment of >= 1% gene modified cells.

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

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

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

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

Measure: 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

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

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

Measure: Presence of confirmed replication competent lentivirus

Time: Up to 15 years

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

Measure: Presence of insertional mutagenesis

Time: Up to 15 years

Measure: 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

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

Measure: 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

Time: Up to 15 years

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 P140K

Inclusion Criteria: - 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 - 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 Exclusion Criteria: - 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 - 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 Inclusion Criteria: - 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 - 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 Exclusion Criteria: - 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 - 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 Human Immunodeficiency Virus 1 Positive Stage I Adult Hodgkin Lymphoma Stage I Adult Non-Hodgkin Lymphoma Stage II Adult Hodgkin Lymphoma Stage II Adult Non-Hodgkin Lymphoma Stage III Adult Hodgkin Lymphoma Stage III Adult Non-Hodgkin Lymphoma Stage IV Adult Hodgkin Lymphoma Stage IV Adult Non-Hodgkin Lymphoma HIV Infections Acquired Immunodeficiency Syndrome Lymphoma Lymphoma, Non-Hodgkin Hodgkin Disease PRIMARY OBJECTIVES: I. 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. --- P140K ---

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

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. --- P140K ---



HPO Nodes


HPO:
Hodgkin lymphoma
Genes 15
ATM TCF4 POLE FAS DKC1 CASP10 TCF4 FAS FASLG COL14A1 RNF43 AAGAB RASGRP1 PRKCD KLHDC8B
Lymphoma
Genes 133
ATM KRAS CD19 IGH DDX41 BCL10 BIRC3 FOXP1 MS4A1 TP63 RAG1 LIG4 NFKB2 MSH6 TERC RECQL4 NTHL1 WIPF1 CTC1 LYST NOP10 RASGRP1 TNFRSF1B XRCC4 PRKCD NHP2 MAGT1 TNFRSF13B IGH RMRP RUNX1 CTLA4 DCLRE1C FAS ICOS RNF43 NSUN2 XIAP IL7R CASP10 BCL6 CDKN2A ATM IL2RG RTEL1 PARN NBN KIT TNFRSF13C TCF4 ICOS TNFSF12 CHEK2 USB1 CD19 CR2 NRAS MSH2 WAS BCL10 CASP10 MYD88 COL14A1 PRKCD TNFRSF13B MYC MDM2 SH2D1A CCND1 BCL10 CFTR CD27 PGM3 TCF4 CHD7 IGH LIG4 BLM BCL2 TET2 HLA-DRB1 PRSS1 NPM1 KIF11 ITK WRAP53 RAD54B TINF2 FAS DKC1 APC CD81 LIG4 BLM CD28 DKC1 AAGAB RAG2 TNFRSF1B MLH1 TNFRSF13C DNASE1L3 NFKB1 PMS2 ASXL1 IL2RG PRF1 PTEN MALT1 RAD54L CTLA4 CD28 PNP SRSF2 TNFSF12 STAT3 POLE ADA CR2 ADA FASLG PIK3R1 TP53 CTRC ZAP70 MYD88 RB1 RMRP SPINK1 TERT KLHDC8B NBN RHOH
Non-Hodgkin lymphoma
Genes 32
ATM FAS CASP10 CTLA4 FAS BCL10 CD28 BIRC3 FOXP1 TNFRSF1B MYC CCND1 ASXL1 ATM MALT1 CTLA4 CD28 SRSF2 KIT POLE IGH ADA TET2 FASLG PIK3R1 NTHL1 RASGRP1 TNFRSF1B PRKCD NBN RHOH IGH