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Treatment group 1 (300 mcg/kg/day) of a two-arm, dose-escalation pilot feasibility trial of TXA127 (Angiotensin 1-7) in subjects undergoing double cord blood transplantation for the treatment of a variety of hematologic malignancies for whom there is no available therapy with substantive anti-disease effect.

Treatment group 2 (1000 mcg/kg/day) of a two-arm, dose-escalation pilot feasibility trial of TXA127 (Angiotensin 1-7) in subjects undergoing double cord blood transplantation for the treatment of a variety of hematologic malignancies for whom there is no available therapy with substantive anti-disease effect.

TXA127 300 mcg/kg/day

TXA127 1000 mcg/kg/day

Uday R Popat, MD

The purpose of this study is to evaluate the effect of TXA127 on neutrophil and platelet counts in adult patients who have undergone a double cord blood transplant. The study will also evaluate the effect of TXA127 on chemotherapy-induced mucositis, an inflammation of the mucous membranes in the digestive tract (mouth to anus) and immune reconstitution which helps patients fight infections. For patients undergoing CBT, both neutrophil and platelet normalization and immune reconstitution can be delayed. TXA127 has shown to be well tolerated by patients and appears to induce a rapid production of neutrophils and platelets in the bloodstream as well as increase the immune system components. It has also been shown to reduce the severity of chemotherapy-induced mucositis.

Cord blood as a hematopoietic stem cell source has multiple advantages. Cord blood is normally discarded at birth and can easily be collected and stored. Availability of numerous CB banks has resulted in genetically diverse CB units including those from non-Caucasians. Once a suitable CB unit is located, confirmatory typing can be quickly performed and a donor unit can be shipped to the transplant center. Furthermore, because a CB graft results in a lower incidence of graft-versus-host-disease, one or two antigen-mismatched units are acceptable for transplantation. Despite these advantages, CB has a significant drawback which is that the number of hematopoietic stem cells obtained from a unit of CB is significantly lower than from a bone marrow (BM) harvest or peripheral blood stem cell (PBSC) harvest. Both engraftment and immune reconstitution are delayed in patients undergoing CB transplant. TXA127 is pharmaceutically-formulated angiotensin 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. The hematopoietic properties demonstrated in preclinical and clinical studies support the investigation of TXA127 to reduce time to neutrophil and platelet engraftment following transfusion of limited number of CD34+ cells.

TXA127 in Enhancement of Engraftment in Adult Double Cord Blood Transplantation

Phase I Evaluation of the Safety and Efficacy of TXA127 (Angiotensin 1-7) to Enhance Engraftment in Adults Undergoing Double Cord Blood Transplantation

The safety and tolerability profile of TXA127 will be provided by descriptively summarizing, at a minimum, the following outcomes: 1) number and proportion of patients with adverse events presented by preferred term, by system organ class (SOC), and by severity grade and relationship to TXA127, as assessed by the Investigator; 2) number and proportion of patients terminating TXA127 due to adverse events related to TXA127; 3) Day 100 treatment-related mortality (TRM) rate; 4) Day 100 mortality rate; 5) number of red blood cell and other blood component transfusions; 6) incidence of infection.

Platelet transfusion requirements based on units of platelets transfused and days of platelet transfusions

Immune reconstitution will be assessed via the measurement of peripheral blood concentrations of CD3+, CD4+, CD8+, CD19+, and CD56+ cells (performed at Study Days 62 and 100).

Incidence of mucositis is defined by the occurrence of least one adverse event with MedDRA preferred term that includes "mucositis" or "stomatitis". The severity grade will be determined by NCI-CTCAE.

Incidence, severity and duration of aGVHD will be reported as a proportion (with 95% CIs) of subjects with Grade II-IV aGVHD. All incidents of aGVHD will at a minimum be listed, with the severity and time course included.

Time to neutrophil engraftment and platelet recovery

Constant Therapeutics LLC

Tarix Pharmaceuticals

Hematologic Neoplasms

Bone Marrow Failure Disorders

Pancytopenia

Cytopenia

Eltrombopag will be given orally as a single daily dose. From day +1 after cord blood transplantation, start eltrombopag 100 mg/d. If primary end point not reached on day +14,then from day +15 - 150 mg/d. If primary end point not reached on day +28 then from day +29 - 200 mg/d. If primary end point not reached on day +42 then from day +43 and on - 300 mg/d (maximal dose). If dose not tolerated, return to last tolerated dose.

Eltrombopag will be discontinued after platelet count has exceeded 50,000/microliter for 14 consecutive days without administration of platelets.

In case of decline of platelet count \< 30,000/microliter within 15 days from eltrombopag discontinuation, it will be resumed for additional 4 weeks.

After 4 weeks we will re-attempt to hold the drug.

From day +1, start eltrombopag 100 mg/d. If primary end point not reached on day +14, then from day +15 - 150 mg/d.

If primary end point not reached on day +28 then from day +29 - 200 mg/d. If primary end point not reached on day +42 then from day +43 and on - 300 mg/d maximal dose).

If present dose not tolerated, return to last tolerated dose. Eltrombopag will be discontinued after platelet count has exceeded 50,000/microliter for 14 consecutive days without administration of platelets. In case of decline of platelet count \< 30,000/microliter within 15 days from eltrombopag discontinuation, it will be resumed for additional 4 weeks. After 4 weeks we will re-attempt to hold the drug (if the threshold of platelet count \>50,000/microliter will be reached again).

Eltrombopag

Moshe Yeshurun, MD

Ron Ram, MD

Michael Shapira, MD

The purpose of this study is to determine whether Eltrombopag may shorten time to platelet engraftment after allogeneic cord blood transplantation.

Platelet recovery is significantly hampered following umbilical cord blood (UCB) transplantation. Median time to platelet engraftment (defined as the first of 7 consecutive days of an unsupported platelet count of at least 20,000/microliter) in a large retrospective study was more than 70 days and cumulative incidence of platelet recovery at 6 months was 50.5%. In the pediatric population with acute leukemia median time to platelet engraftment with UCB transplantation was 59 days and cumulative incidence of platelet recovery at 6 months was 43%-73%, depending on human leukocyte antigen (HLA) disparity and cell dose. Recently, in a cohort of adult patients given myeloablative conditioning followed by double UCB transplantation, the cumulative incidence of platelet recovery (≥ 50,000/microliter)at 100 days was 53%. In another cohort of patients given reduced intensity conditioning regimen followed by single or double UCB transplantation, the median time to platelet recovery (≥ 50,000/microliter) and cumulative incidence of platelet recovery at 6 months were 49 days and 65%, respectively. Thus, after UCB transplantations, patients are platelet transfusion-dependent for prolong periods of time, resulting in many drawbacks, such as exposure to blood transfusions hazards, higher incidence of platelet allo-reactivity and extended periods of bleeding diathesis and undesirable costly and long hospitalizations.

Eltrombopag is a thrombopoietin-receptor agonist that initiates thrombopoietin-receptor signaling and thereby inducing proliferation and maturation of megakaryocytes.Administration of eltrombopag increased platelet production in volunteers with normal platelet counts, patients with thrombocytopenia secondary to hepatitis C virus infection and in patients with chronic immune thrombocytopenic purpura.

We will evaluate the safety and efficacy of eltrombopag treatment given early after UCB transplantation. The study is an open non-comparative study. The primary outcome will be cumulative incidence of partial platelet engraftment (first of 7 consecutive days of an unsupported platelet count of at least 20,000/microliter)at day 50 post transplantation. Secondary objectives are safety, tolerability and other transplantation related outcomes.

Eltrombopag for Enhancing Platelet Engraftment in Adult Patients Undergoing Cord Blood Transplantation

Number of participants with any grade 3/4 adverse event as a measure of safety and tolerability.

Number of participants with a thromboembolic event as a measure of safety.

Rabin Medical Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TXA127 in Enhancement of Engraftment in Adult Double Cord Blood Transplantation	NCT01300611	Double Cord Blo... Acute Myelogeno... Myelodysplastic... Myelofibrosis Acute Lymphobla... Chronic Myelocy... Non Hodgkins Ly... Hodgkins Lympho... Chronic Lymphoc...	TXA127 300 mcg/... TXA127 1000 mcg...	18 Years - 60 Years	Tarix Pharmaceuticals
Eltrombopag for Enhancing Platelet Engraftment in Adult Patients Undergoing Cord Blood Transplantation	NCT01757145	Hematological M... Bone Marrow Fai...	Eltrombopag	18 Years -	Rabin Medical Center
TXA127 in Enhancement of Engraftment in Adult Double Cord Blood Transplantation	NCT01300611	Double Cord Blo... Acute Myelogeno... Myelodysplastic... Myelofibrosis Acute Lymphobla... Chronic Myelocy... Non Hodgkins Ly... Hodgkins Lympho... Chronic Lymphoc...	TXA127 300 mcg/... TXA127 1000 mcg...	18 Years - 60 Years	Tarix Pharmaceuticals

Spots Global Cancer Trial Database for platelet engraftment