Evaluation of the Safety and Efficacy of TXA127 (Angiotensin 1-7) to Enhance Engraftment in Pediatric Patients Undergoing Single or Double Umbilical Cord Blood Transplantation

Engraftment failure is a major obstacle to the success of cord blood transplantation in children with malignancies and inherited metabolic disorders, despite the fact that they receive relatively high doses of nucleated cells from UCB. TXA127 is pharmaceutically formulated Angiotensin 1-7 [A(1-7)], a non-hypertensive derivative of Angiotensin-II (which contains the 8th amino acid conferring receptor binding to blood pressure receptors). TXA127 has multilineage effects on hematopoietic progenitors in vitro and in vivo. Preclinical data show that TXA127 is a novel stimulator of early multilineage hematopoietic progenitors, increases engraftment of committed hematopoietic progenitors, and induces more rapid production of platelets and neutrophils in the peripheral circulation, especially in limited cell number transplants. Treatment with TXA127 following UCBT is expected to increase the numbers of hematopoietic progenitors and accelerate engraftment.

Study Overview

• Status: Withdrawn
• Conditions: Hematologic Malignancy; Cord Blood Transplant; Inherited Metabolic Disease
• Intervention / Treatment: Drug: TXA127

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Pediatric Bone and Cord Blood, Duke Univ. Med. Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject, parent, or legal guardian provided written informed consent.
• Subjects must be >6 months and <21 years of age.

• Subjects must have one or two available 4, 5, or 6/6 antigen matching unrelated UCB unit(s) that will deliver a cell dose between 3.0-5.0 x 107cells/kg.

  • These units must be HLA-matched minimally at 4 of 6 HLA-A and B (at intermediate resolution by molecular typing) and DRB1 (at high resolution by molecular typing) loci with the subject.
  • If two CB units will be used, the units must be HLA-matched at 3 of 6 HLA- A, B, and DRB1 loci with each other (using same resolution of molecular typing as indicated above).
  • For a single unit transplant, a minimum of 3 x 107cells/kg will be required.
  • For a double unit transplant, HLA-matched units must be available such that together both units deliver a combined pre-cryopreserved nucleated cell dose of at least 4.0 x 107 cells/kg with 1 unit of at least 2.5 x 107 cells/kg and the other at least 1.5 x 107 cells/kg.
• Subjects must have histologically confirmed diagnosis of a hematologic malignancy or a laboratory confirmed inherited metabolic disease.
• Subjects who have had a prior autologous or allogeneic transplant are allowed to participate provided it has been >1 year since the transplant was completed.
• Subjects must not have active CNS disease at the time of study enrollment.
• Subjects must have a life expectancy of >4 months.

• Female subjects capable of reproduction (defined as a subject who has started menses) must agree to the following:

  • Use of an effective oral or IM contraceptive method during the course of the study and 2 months following the last administration of study drug.
  • Female subjects capable of reproduction must have a negative pregnancy test result within 3 days prior to first study drug dose.

• Subjects must have adequate function of other organ systems as measured by:

  • Creatinine <2.0 mg/dL and creatinine clearance >50 mL/min.
  • Hepatic transaminases (ALT/AST) <4 x ULN, bilirubin <2.0 mg/dL.
  • Adequate cardiac function by echocardiogram or MUGA scan (ejection fraction or shortening fraction >80% of normal value for age).
  • Pulmonary function tests demonstrating FVC and FEV1 of >60% of predicted. DLCO should be used for subjects >10 years old. Crying vital capacity of >60% may be substituted for subjects unable to complete PFTs.

Exclusion Criteria:

• Subjects with an uncontrolled infection at the time of cytoreduction.
• Subjects who are pregnant or breast feeding.
• Subjects who are known to be seropositive for HIV or HTLV-1.
• Subjects who have had an autologous or allogeneic transplant <1 year from the anticipated administration of the first dose of study drug.
• Subjects who have received treatment with an investigational agent within 30 days of anticipated administration of the first dose of study drug.
• Subjects with current alcohol use, illicit drug use or any other condition (e.g., psychiatric disorder) that, in the opinion of the Investigator, may interfere with the subject's ability to comply with the study requirements or visit schedule.
• Subjects must not have any co-morbid condition which, in the view of the Principal Investigators, renders the subject at too high a risk from treatment complications and regimen-related morbidity/mortality.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 300mcg/kg/day for 28 days	Drug: TXA127; 300mcg/kg/day, subcutaneous injection for up to 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety of TXA127 in subjects undergoing cord blood transplantation	Through Day 100 post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of TXA127 on incidence, severity and duration of aGVHD		Through Day 100 post transplant
Effect of TXA127 on incidence, severity and duration of mucositis	WHO oral toxicity score	Through Day 100 post transplant
Effect of TXA127 on neutrophil engraftment		Through Day 100 post transplant
Effect of TXA127 on platelet recovery		Through Day 100 post transplant
Effect of TXA127 on immune reconstitution		Through Day 100 post transplant

Collaborators and Investigators

• Sponsor: Tarix Pharmaceuticals
• Investigators: Principal Investigator: Kristin Page, MD, Duke University

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: March 12, 2012
• First Submitted That Met QC Criteria: March 12, 2012
• First Posted (Estimate): March 14, 2012

Study Record Updates

• Last Update Posted (Estimate): August 31, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Mucositis; hematological malignancy; Immune reconstitution; Cord blood transplant; inherited metabolic disease; Neutrophil engraftment; Platelet recovery
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Metabolic Diseases; Antihypertensive Agents; Vasodilator Agents; Angiotensin I (1-7)
• Other Study ID Numbers: TXA127-2010-002