A Study Evaluating the Safety of Cal-1 (LVsh5/C46) Drug Product in HIV-1 Infected Patient With High Risk Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and the feasibility, and the success of engraftment of the introduction of Cal-1 gene-transduced haematopoietic cell populations (Ttn and HSPCtn) in patients with HIV-1-related high-risk lymphoma.

Detailed Description
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not provided

Official Title
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A Phase I/II Study of the Safety of CD34+ Haematopoietic Stem/Progenitor Cells and CD4+ T Lymphocytes Transduced With LVsh5/C46, a Dual Anti-HIV Gene Transfer Construct, in HIV-1 Infected Patients With High-risk Lymphoma

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Cal-1 (LVsh5/C46) drug product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible subjects will undergo screening assessments at three time points: Screening 1 at the beginning of chemotherapy, Screening 2 (first check-point) after the harvest for CD34, Screening 3 (second check-point) before the ASCT procedure. Potential subjects must satisfy all of the inclusion criteria to be enrolled in the study and proceed with the first apheresis (day -39). In-A. Prior to any study-related procedures, signed informed consent indicating that they understand the purpose, risks and procedures required for the study and are willing to participate in the study In-B. Individuals aged 18 to 60 years of age (inclusive) at time of consent In-C. Women with child-bearing potential must be on adequate effective contraception (continuous progestative contraception) In-D. Documented HIV-1 infection at or before the time of lymphoma diagnosis In-E. Treatment with antiretroviral agents (excluding NNRTI) introduced or optimized at the time of screening In-F. Biopsy-proven lymphoma meeting one of the following criteria: 1. Intermediate- or high-grade B-cell non-Hodgkin lymphoma, meeting 1 of the following criteria: in first complete remission with high-risk features such as T-cell lymphoma and plasmablastic lymphoma (after multidisciplinary consultation regarding the indication of ASCT in this context). The decision of ASCT is independent of the present clinical trial. in partial remission relapsed after initial complete remission failed induction therapy but responds to salvage therapy (i.e., chemosensitive disease) Hodgkin lymphoma, meeting 1 of the following criteria: in first or greater relapse after initial complete remission in partial remission failed induction therapy but responds to salvage therapy (i.e. chemosensitive disease) High-risk lymphoma requiring a treatment with combined chemotherapy and autologous stem cell transplantation (ASCT) Exclusion Criteria: Ex-A. -Left ventricular ejection fraction <50% at Screening 1: Ex-B. Abnormal biochemistry at Screening 1: Alanine and/or aspartate aminotransferase (ALT/AST) >10 x upper limit of normal (ULN) Total bilirubin > 2.5 x ULN Creatinine clearance <60ml/min Ex-C. Severe coagulopathy Ex-D. Prothombin time > 2x ULN Ex-E. Evidence of co-infection with hepatitis B virus (HBsAg+), hepatitis C virus, West Nile Virus, or Human T-lymphotropic virus (HTLV-1) as detected at Screening 1 Ex-F. Stay in West Nile Virus endemic area less than 6 weeks prior to CD34+ collection Ex-G. Evidence of non-treated opportunistic infection during the pre-infusion period Ex-H. Evidence of not-treated CNS involvement of lymphoma at Screening 1 Ex-I. Isolated CNS relapse of the lymphoma without other evidence of active disease at Screening 1 Ex-J. Known hypersensitivity to G-CSF (Neupogen™) or plerixafor (Mozobil™) Ex-K. Evidence of uncontrolled HIV-1 viremia at screening 2 and/or 3 (plasma HIV-1 RNA ≥ 1.000 copies/ml confirmed in 2 successive blood samples) Ex-L. Evidence of chemoresistant lymphoma at screening 2 Ex-M. Any contra-indication to ASCT at any time during the pre-infusion period Ex-N. Participation in any study involving any investigational drug or medical device within 3 months prior to Screening 1 Ex-O. Receipt of a vaccine for HIV-1 or any gene transfer product at any time Ex-P. Subjects who will not accept transfusions of blood products Ex-Q. Pregnant or breast-feeding woman at any time Ex-R. Woman of child-bearing potential not under adequate contraceptive protection at any time Ex-S. Inability to understand and provide informed consent Psychological or psychiatric disability thought to be clinically significant in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cal-1( LVsh5/C46) drug product<br> | Drug: Cal-1 (LVsh5/C46) drug product<br>* Autologous CD34+ Haematopoietic Stem/Progenitor Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46, a Dual Anti-HIV Gene Transfer Construct<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse event post transplant | to evaluate the procedure safety | 24 months post-transplant | 
| Success of hematopoietic stem cell engraftment | evaluation of Cal-1 marking and expression in peripheral blood subpopulations (monocytes, CD4+ and CD8+ lymphocytes) | 24 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 24 months post-transplant | 
| Absence of detection of vector-derived Replication competent lentivirus (RCL) |  | 24 months post-transplant | 
| Frequency and severity of clinical adverse events | as assessed by the United States national Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) | 24 months post-transplant | 
| Absence of tropism shift from R5 to dual/mixed or X4 at any point after Day 0 |  | 24 months post-transplant | 
| Quantify gene transfer efficiency and expression | extent of HSPCtn and Ttn survival as measured by Cal-1 marking and expression in peripheral blood | 24 months post-transplant | 
| Time to restart antiretroviral therapy |  | 24 months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, Lymphoma, Gene therapy