In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)

• ClinicalTrials.gov Identifier: NCT02986698
• Recruitment Status: Enrolling by invitation
• First Posted: December 8, 2016
• Last Update Posted: May 22, 2023
• Sponsor: University of California, San Francisco
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Tippi Mackenzie, University of California, San Francisco

Tracking Information

• First Submitted Date: December 5, 2016
• First Posted Date: December 8, 2016
• Last Update Posted Date: May 22, 2023
• Actual Study Start Date: October 5, 2017
• Estimated Primary Completion Date: March 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 7, 2016)

• Maternal participant tolerance of bone marrow harvest [ Time Frame: 5 year recruitment phase to include time of bone marrow harvest through 30 days after delivery ]
  Maternal participant tolerance of bone marrow harvest defined as not requiring interventions for preterm labor, bleeding, infection or prolonged hospitalization.
• Safety of in utero hematopoietic stem cell transplantation when performed at the same time as in utero blood transfusion for the fetal participant [ Time Frame: 5 year recruitment plus 1 year data collection phase to include time of IUHCT through 1 year after delivery ]
  safety for fetal participant defined by survival 24 hours after procedure, fetal survival till birth, neonatal survival through discharge of hospitalization and no evidence of graft versus host disease

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 7, 2016)

• Adequate bone marrow harvest from the maternal participant [ Time Frame: 5 year recruitment phase ]
  This is defined as approximately 200-300 cc of bone marrow from which 10^7-10^9 CD34+ cells/kg fetal weight with 10^5-10^7 CD3+ cells/kg fetal weight will be isolated.
• successful engraftment [ Time Frame: 5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery ]
  The primary efficacy endpoint is successful engraftment of maternal bone marrow- derived CD34+ hematopoietic stem cells measured by establishment of maternal participant donor cell chimerism equal to or greater than 1% donor cells in the circulation of the fetal recipient. Chimerism will be determined in cord blood at birth, or at a corrected gestational age of 40 weeks, if there is preterm delivery, followed weekly for the first 4 weeks of life, and monthly for one year in the infant to monitor the stability of engraftment.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
• Official Title: A Single-Center, Non-Randomized Study of the Safety and Efficacy of In Utero Hematopoietic Stem Cell Transplantation for the Treatment of Fetuses With Alpha Thalassemia Major
• Brief Summary: The investigators aims to evaluate the safety of in utero hematopoietic stem cell transplantation in fetuses with alpha-thalassemia major performed at the time of in utero transfusion of red blood cells.

Detailed Description

Alpha thalassemia major (ATM) is almost universally fatal in utero and represents an orphan disease with an unmet need for effective therapies. The only current treatment to allow the fetus to be born is to perform in utero transfusions (IUT) of red blood cells to treat the anemia and avoid the complications of hydrops and fetal demise. Often, affected pregnancies undergo elective termination after diagnosis. Cases with prenatal diagnosis of ATM who receive IUT and survive to birth will ultimately require lifelong monthly blood transfusions or bone marrow transplant, if a suitable donor is identified.

This is a phase 1 clinical trial to demonstrate the safety, feasibility and efficacy of performing in utero stem cell transplantation on fetuses affected with ATM. The investigators aim to recruit ten participants with a prenatal diagnosis of ATM. Participants will undergo bone marrow harvest and an in utero transfusion combined with maternal stem cells. Transplanting maternal cells into the fetus takes advantage of existing maternal-fetal tolerance during pregnancy. Hematopoietic stem cell (HSC) transplantation into the fetus takes advantage of the developing fetal immune system to induce tolerance to the transplanted cells without using conditioning or immunosuppression. Performing stem cell transplantation at the same time as IUT minimizes any additional procedural risk to the fetus.

The investigators hope to demonstrate that it is safe and feasible to perform in utero stem cell transplantation. Additionally, the investigators want to demonstrate postnatal chimerism of maternal cells so that, if a bone marrow transplant remains necessary after delivery, conditioning and immune suppression will not be required.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Alpha Thalassemia Major
• Hemoglobinopathy; With Thalassemia
• Hemoglobinopathies
• Fetal Anemia
• Fetal Hydrops
• Alpha; Thalassemia
• Thalassemia Major
• Thalassemia Alpha
• A-Thalassemia

Intervention

Biological: in utero hematopoietic stem cell transplantation

This is a phase 1 safety study to demonstrate it is safe for both the mother and fetus to perform In utero hematopoietic stem cell transplantation of maternal derived stem cells at the time of intrauterine transplantation of red blood cells to treat fetuses affected with alpha-thalassemia major.

Study Arms

Experimental: in utero hematopoietic stem cell transplantation

Perform in utero hematopoietic stem cell transplantation at the time of intrauterine transplantation in fetuses with alpha-thalassemia major. The cellular product is: Semi-allogeneic, Related, Maternal Bone Marrow-Derived, Miltenyi CliniMACS Plus enriched CD34+ hematopoietic stem cells administered in utero at a dose of 1 x 10^7-10^9 cells/kg fetal weight with equal to or less than 1% CD3+ T cells (equivalent to 10^5-10^7 T cells/kg fetal weight) in a final volume of 2-5ml suspended in 5% human serum albumin in Normosol buffer (Hospira, Inc.).

Stem cells will be administered immediately before the red blood cells intravenously via the umbilical vein during the clinically indicated IUT. All participants will receive one dose of stem cells but may receive additional transfusions as clinically indicated.

Intervention: Biological: in utero hematopoietic stem cell transplantation

Publications *

• Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol. 2015 Jan 12;5:278. doi: 10.3389/fphar.2014.00278. eCollection 2014.
• Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev. 2012 Apr;26 Suppl 1:S31-4. doi: 10.1016/S0268-960X(12)70010-3.
• MacKenzie TC. Fetal Surgical conditions and the unraveling of maternal-fetal tolerance. J Pediatr Surg. 2016 Feb;51(2):197-9. doi: 10.1016/j.jpedsurg.2015.10.059. Epub 2015 Nov 4.
• MacKenzie TC, David AL, Flake AW, Almeida-Porada G. Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy. Front Pharmacol. 2015 Feb 10;6:15. doi: 10.3389/fphar.2015.00015. eCollection 2015. No abstract available.
• Jeanty C, Derderian SC, Mackenzie TC. Maternal-fetal cellular trafficking: clinical implications and consequences. Curr Opin Pediatr. 2014 Jun;26(3):377-82. doi: 10.1097/MOP.0000000000000087.
• Nijagal A, MacKenzie TC. Clinical implications of maternal-fetal cellular trafficking. Semin Pediatr Surg. 2013 Feb;22(1):62-5. doi: 10.1053/j.sempedsurg.2012.10.011.
• Nijagal A, Flake AW, MacKenzie TC. In utero hematopoietic cell transplantation for the treatment of congenital anomalies. Clin Perinatol. 2012 Jun;39(2):301-10. doi: 10.1016/j.clp.2012.04.004. Epub 2012 May 8.
• Nijagal A, Wegorzewska M, Le T, Tang Q, Mackenzie TC. The maternal immune response inhibits the success of in utero hematopoietic cell transplantation. Chimerism. 2011 Apr;2(2):55-7. doi: 10.4161/chim.2.2.16287.
• Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, Vichinsky E. Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature. Prenat Diagn. 2016 Dec;36(13):1242-1249. doi: 10.1002/pd.4966. Epub 2016 Dec 7.

Recruitment Information

• Recruitment Status: Enrolling by invitation
• Estimated Enrollment (submitted: December 7, 2016): 10
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2026
• Estimated Primary Completion Date: March 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female fetuses from 18 weeks and 0/7 days to 26 weeks 0/7 days gestation with a diagnosis of alpha-thalassemia major by chorionic villus sampling (CVS), amniocentesis, cordocentesis or by identification of parents as genetic carriers, and identification of fetal anemia or signs of impending hydrops, for whom parents elect to pursue in utero transfusion, and are willing to undergo subsequent IUT for the remainder of gestation.
• parents must consent to fetal autopsy in the event of a fetal demise
• adequate bone marrow harvest from maternal participant is a condition for inclusion

Exclusion Criteria:

• Fetal Subject Exclusion Criteria: Fetal participants will be excluded if they have a second major anatomic anomaly (not related to the underlying thalassemia) that contributes a significant morbidity or mortality risk, or echocardiogram or ultrasound findings that indicate a high risk of fetal demise after fetal intervention.
• Maternal Subject Exclusion Criteria: Maternal participants will be excluded if they have one or more morbidities that would preclude bone marrow harvest and fetal intervention including, but not limited to, morbid obesity with BMI > 35, maternal cardiac disease, mirror syndrome, symptomatic maternal anemia, or if they develop preterm premature rupture of membranes (PPROM) or active preterm labor (PTL).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Weeks to 26 Weeks (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02986698
• Other Study ID Numbers: 16-21157
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Tippi Mackenzie, University of California, San Francisco
• Original Responsible Party: Tippi Mackenzie, University of California, San Francisco, Associate Professor of Surgery
• Current Study Sponsor: University of California, San Francisco
• Original Study Sponsor: Same as current
• Collaborators: California Institute for Regenerative Medicine (CIRM)

Investigators

• Principal Investigator: Tippi Mackenzie, MD; University of California, San Francisco

• PRS Account: University of California, San Francisco
• Verification Date: May 2023