Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances

• ClinicalTrials.gov Identifier: NCT03164135
• Recruitment Status: Recruiting
• First Posted: May 23, 2017
• Last Update Posted: May 23, 2017
• Sponsor: Affiliated Hospital to Academy of Military Medical Sciences
• Collaborators: Peking University; Capital Medical University
• Information provided by (Responsible Party): Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences

Tracking Information

• First Submitted Date: May 18, 2017
• First Posted Date: May 23, 2017
• Last Update Posted Date: May 23, 2017
• Estimated Study Start Date: May 30, 2017
• Estimated Primary Completion Date: May 20, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 22, 2017)

Persistence of CCR5 gene disruption in engrafted cells [ Time Frame: 12 months ]

Participants will be transplanted with CD34+ cells which are treated using the CRISPR/Cas9 system to disrupt CCR5 gene. The persistence of CCR5 gene disruption in engrafted cells will be evaluated by sequencing.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: May 22, 2017)

CD34+ cell number [ Time Frame: the first month ]

The CD34+ cell number pre-infusion

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 22, 2017)

• Gene disruption efficiency of bone marrow cells [ Time Frame: Up to Month 12 ]
  The percentage of disrupted CCR5 gene alleles in genome from bone marrow cells detected by sequencing.
• CCR5 gene disruption efficiency of peripheral blood cells [ Time Frame: Up to Month 12 ]
  The percentage of disrupted CCR5 gene alleles in genome of peripheral blood cells by sequencing.
• Hematopoietic cell engraftment [ Time Frame: Up to Year 3 ]
  Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery
• HIV-1 RNA level [ Time Frame: Up to Year 3 ]
  Level change of HIV-1 RNA in plasma after transplantation
• CD4+ T cell number [ Time Frame: Up to Year 3 ]
  Level change of the CD4+ T cell number after transplantation
• The ratio change of CD4/CD8 [ Time Frame: Up to Year 3 ]
  The ratio change of CD4/CD8 in peripheral blood after transplantation
• HIV-1 RNA levels during ATI [ Time Frame: Every two weeks, until the end of ATI or up to 3 months ]
  HIV-1 RNA levels in plasma during ATI.
• HIV-1 DNA level [ Time Frame: Up to Month 12 ]
  Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances
• Official Title: Safety and Feasibility Study of Allotransplantation of CRISPR/Cas9 CCR5 Gene Modified CD34+ Hematopoietic Stem/Progenitor Cells in HIV-infected Subjects With Hematological Malignances
• Brief Summary: The investigators performed this study to evaluate the safety and feasibility of transplantation with CRISPR/Cas9 CCR5 gene modified CD34+ hematopoietic stem/progenitor cells for patients that develop AIDS and hematological malignances. Patients will be treated with antiviral therapy (ART) to achieve undetectable HIV-1 virus in peripheral blood before conditioning. CD34+ cells from donors will be infused into the patients after treatment with CRISPR/Cas9 to ablate CCR5 gene.
• Detailed Description: The primary objective of this study is to determine the safety of the infusion of CD34+ cells which are treated with CRISPR/Cas9 to disrupt the CCR5 gene. The secondary objective is to evaluate the resistance to HIV-1(R5) in infected patients after infusion of modified CD34+ cells with or without an antiretroviral therapy interruption (ATI). After the transplantation, the reconstitution time and frequency of multi-lineage hematopoietic cell will be analyzed against previously reported HSCT in HIV-1 patients. After the detection of high CD4+ T cells reconstitution (over 600 cells/μL) and CCR5 negative cells (over 1%) in peripheral blood, subjects will undergo an ATI. HIV-1 RNA level and CD4+ cell counts will be monitored biweekly for at least one month.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: HIV-1-infection

Intervention

Genetic: CCR5 gene modification

CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 targeting CCR5 gene.

Study Arms

Experimental: CCR5 gene modification

CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.

Intervention: Genetic: CCR5 gene modification

• Publications *: Xu L, Wang J, Liu Y, Xie L, Su B, Mou D, Wang L, Liu T, Wang X, Zhang B, Zhao L, Hu L, Ning H, Zhang Y, Deng K, Liu L, Lu X, Zhang T, Xu J, Li C, Wu H, Deng H, Chen H. CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia. N Engl J Med. 2019 Sep 26;381(13):1240-1247. doi: 10.1056/NEJMoa1817426. Epub 2019 Sep 11.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 22, 2017): 5
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 20, 2021
• Estimated Primary Completion Date: May 20, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age between 18 to 60, male of female;
2. Hematological neoplasms;
3. HIV-1 R5 tropic virus with no CXCR4-tropic or R5/X4 dual-tropic HIV;
4. On ART with undetectable HIV-1 level (<40gc/ml, HIV-1 RNA);
5. Availability of a consenting HLA-matched donor;
6. No cardiomyopathy or congestive heart failure;
7. CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL;
8. Absence of psychosocial conditions and be willing to comply with study-mandated evaluations for 2 years;
9. Life expectancy of at least 1 year.

Exclusion Criteria:

1. Acute or chronic hepatitis B or hepatitis C infection;
2. Any cancer or malignancy other than hematological neoplasms;
3. Subject with CMV retinitis or other active CMV infection related diseases;
4. Subject with organ dysfunction;
5. Non-pregnant and non-nursing;
6. Drug or alcohol abuse or dependence;
7. Currently enrolled in another clinical trial or underwent cell therapy;
8. Donor incapable for HSPC mobilization;
9. in the opinion of the site investigator, would interfere with adherence to study requirements.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Bin Zhang, MD, PhD; +86-10-66947625; zb307ctc@163.com

Contact: Hu Chen, MD, PhD; +86-10-66947108; chenhu217@aliyun.com

• Listed Location Countries: China

Administrative Information

• NCT Number: NCT03164135
• Other Study ID Numbers: 307-HSPC-R5
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences
• Study Sponsor: Affiliated Hospital to Academy of Military Medical Sciences

Collaborators

• Peking University
• Capital Medical University

• Investigators: Not Provided
• PRS Account: Affiliated Hospital to Academy of Military Medical Sciences
• Verification Date: May 2017