Phase I Study of Eltrombopag for Promoting Thrombopoiesis After Total Body Irradiation

• Sponsor: Jane Liesveld (Other)
• Overall Status: Completed
• CT.gov ID: NCT00903929
• Collaborator: (none)
• Enrollment: 19
• Arm: 1
• Duration (Months): 72

Study Details

Study Description

Brief Summary

Patients who undergo total body irradiation (TBI) for stem cell transplantation have prolonged periods of low counts of specific blood cells called platelets. These low platelets counts can cause bleeding and infection. Thus far, no drug is available for use to speed the recovery of platelets, and therefore transfusions are often necessary.

The purpose of this study is to test the safety of a drug called eltrombopag in patients who have received TBI. The investigators want to find out what effects, good or bad, it has on people with low platelet counts due to treatment with TBI. The investigators will also be testing how well eltrombopag may work at different doses and determine if this drug speeds up the recovery of the platelets.

Condition or Disease	Intervention/Treatment	Phase
Thrombocytopenia; Acute Radiation Syndrome	Drug: Eltrombopag	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Eltrombopag for Promoting Thrombopoiesis in Patients Undergoing Stem Cell Transplantation After Total Body Irradiation
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eltrombopag	Drug: Eltrombopag; dose escalation

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Eltrombopag [1.5 years]

   The MTD was defined as the highest dose if no dose limiting toxicity was observed, or the highest dose at which less than one-third of the patients experienced toxicities not expected in the standard stem cell transplantation setting.

Secondary Outcome Measures

1. Median Time to Platelet Engraftment [1.5 years]

   Determined for all participants who completed at least 75% of the planned doses. Platelet engraftment was as defined by the Center for International Blood and Marrow Transplant Research as the first of 3 consecutive days of a platelet count 20,000/mL without platelet trans-fusions for 7 days and/or the first day of a platelet count 100,000/mL without platelet transfusions for 7 days.

2. Median Number of Platelet Transfusions up to the Day of Engraftment [baseline to day of engraftment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 18

2. Able to give written informed consent for a clinical trial

3. Scheduled to undergo an autologous or an allogeneic stem cell transplantation from a sibling, related donor, or unrelated donor using a conditioning regimen containing at least 400 cGy TBI

4. Transplantation is being performed for one of the following medical conditions:

• Acute myelogenous leukemia

• Acute lymphoblastic leukemia

• Chronic myelogenous leukemia in chronic, accelerated, or blastic phase

• Myelodysplastic syndrome

• Myeloproliferative diseases such as chronic myelomonocytic leukemia, agnogeneic myeloid metaplasia with myelofibrosis, polycythemia vera, or essential thrombocythemia

• Hodgkin's lymphoma

• Non-Hodgkin's lymphoma

• Multiple myeloma

• Chronic lymphocytic leukemia

• Other malignancies or marrow disease such as aplastic anemia where transplant would be appropriate with approval of principal investigator

1. Patients with therapy-related AML or MDS may be included if their prior malignancy has been in remission for at least 12 months. If the remission is less than 12 months, approval of the principal investigator is required. Entry could be allowed if the malignancy is controlled and not expected to relapse e.g. localized prostate cancer treated with XRT.

2. Patients must meet all other pre-transplantation criteria of the transplant center including acceptable tests of heart, liver, kidney, and lung function (Standard screening for HSCT per PI, and co-investigators).

3. Karnofsky performance status must be ≥70%.

Exclusion Criteria:

1. TBI dose less than 400 cGY

2. Cord blood transplantation

3. HIV infection

4. Pregnancy or breastfeeding

5. Creatinine or bilirubin or ALT or AST greater than two times the upper limit of normal, unless the abnormal bilirubin is due to Gilbert's syndrome

6. Active infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents

7. Concomitant enrollment in another therapeutic clinical study except with PI approval

8. Must not have previously received eltrombopag

9. Patients with moderate or severe liver disease (ALT, AST, or bilirubin ≥ 2X the upper limit of normal, unless the abnormal bilirubin is due to Gilbert's syndrome) will be excluded

10. Patients with high risk of thromboembolism based on genetic syndromes , or past thromboembolic disease in the past 6 months will be excluded from the study, with the exception of those with catheter related clots

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Jane Liesveld

Investigators

• Study Director: Yuhchyau Chen, MD,PhD, University of Rochester
• Principal Investigator: Jane Liesveld, MD, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jane Liesveld, Professor M&D-Hematology/Oncology, University of Rochester
• ClinicalTrials.gov Identifier: NCT00903929
• Other Study ID Numbers: RSRB00028043
• First Posted: May 19, 2009
• Last Update Posted: May 5, 2016
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Thrombocytopenia; Radiation Injuries; Acute Radiation Syndrome

Study Results

Participant Flow

Arm/Group Title	Eltrombopag 75 mg	Eltrombopag 150 mg	Eltrombopag 225 mg	Eltrombopag 300 mg
Arm/Group Description	Dose escalation was based on a standard 3+3 design. A group of 3 patients were enrolled at a given dose level; if none of these patients experienced dose-limiting toxicity (DLT), then the dose could be escalated. If 1 of the 3 patients experienced DLT, then 3 more patients would be enrolled at the same dose level. If no additional patients experienced a DLT, then dose escalation could occur, but if 2 or more of the 6 patients experienced a DLT, then that dose would be the MTD.	Dose escalation was based on a standard 3+3 design. A group of 3 patients were enrolled at a given dose level; if none of these patients experienced dose-limiting toxicity (DLT), then the dose could be escalated. If 1 of the 3 patients experienced DLT, then 3 more patients would be enrolled at the same dose level. If no additional patients experienced a DLT, then dose escalation could occur, but if 2 or more of the 6 patients experienced a DLT, then that dose would be the MTD.	Dose escalation was based on a standard 3+3 design. A group of 3 patients were enrolled at a given dose level; if none of these patients experienced dose-limiting toxicity (DLT), then the dose could be escalated. If 1 of the 3 patients experienced DLT, then 3 more patients would be enrolled at the same dose level. If no additional patients experienced a DLT, then dose escalation could occur, but if 2 or more of the 6 patients experienced a DLT, then that dose would be the MTD.	Dose escalation was based on a standard 3+3 design. A group of 3 patients were enrolled at a given dose level; if none of these patients experienced dose-limiting toxicity (DLT), then the dose could be escalated. If 1 of the 3 patients experienced DLT, then 3 more patients would be enrolled at the same dose level. If no additional patients experienced a DLT, then dose escalation could occur, but if 2 or more of the 6 patients experienced a DLT, then that dose would be the MTD.
Period Title: Overall Study
STARTED	3	3	4	9
COMPLETED	3	3	3	6
NOT COMPLETED	0	0	1	3

Baseline Characteristics

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag: dose escalation
Overall Participants	19
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52
Sex: Female, Male (Count of Participants)
Female	12 63.2%
Male	7 36.8%
Region of Enrollment (participants) [Number]
United States	19 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Eltrombopag
Description	The MTD was defined as the highest dose if no dose limiting toxicity was observed, or the highest dose at which less than one-third of the patients experienced toxicities not expected in the standard stem cell transplantation setting.
Time Frame	1.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description
Measure Participants	19
Number [mg/day]	300

2. Secondary Outcome

Title	Median Time to Platelet Engraftment
Description	Determined for all participants who completed at least 75% of the planned doses. Platelet engraftment was as defined by the Center for International Blood and Marrow Transplant Research as the first of 3 consecutive days of a platelet count 20,000/mL without platelet trans-fusions for 7 days and/or the first day of a platelet count 100,000/mL without platelet transfusions for 7 days.
Time Frame	1.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag: dose escalation
Measure Participants	19
Median (Full Range) [days]	16

3. Secondary Outcome

Title	Median Number of Platelet Transfusions up to the Day of Engraftment
Time Frame	baseline to day of engraftment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag: dose escalation
Measure Participants	19
Median (Full Range) [units of platelets]	4

Adverse Events

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag: dose escalation
All Cause Mortality
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	8/19 (42.1%)
Cardiac disorders
pericarditis	1/19 (5.3%)
Gastrointestinal disorders
graft-versus-host disease of the gut	1/19 (5.3%)
gastroparesis	1/19 (5.3%)
Infections and infestations
urosepsis	1/19 (5.3%)
cytomegalovirus infection with fever	1/19 (5.3%)
clostridium difficile infection	1/19 (5.3%)
Renal and urinary disorders
acute renal failure	3/19 (15.8%)
Respiratory, thoracic and mediastinal disorders
acute respiratory distress syndrome	1/19 (5.3%)
Skin and subcutaneous tissue disorders
graft-versus-host disease skin rash	1/19 (5.3%)
Vascular disorders
pumonary embolism	1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	19/19 (100%)
Blood and lymphatic system disorders
edema	3/19 (15.8%)
Cardiac disorders
hypertension	2/19 (10.5%)
Endocrine disorders
hyperglycemia	9/19 (47.4%)
hypertriglyceridemia	2/19 (10.5%)
hypocalcemia	2/19 (10.5%)
hypomagnesemia	2/19 (10.5%)
hypokalemia	5/19 (26.3%)
hypophosphatemia	3/19 (15.8%)
Gastrointestinal disorders
dehydration	2/19 (10.5%)
diarrhea	3/19 (15.8%)
dysphagia	3/19 (15.8%)
mucositis	5/19 (26.3%)
nausea	6/19 (31.6%)
pain	3/19 (15.8%)
General disorders
fatigue	2/19 (10.5%)
Hepatobiliary disorders
alanine aminotransferase elevation	17/19 (89.5%)
Infections and infestations
fever	6/19 (31.6%)
infection with normal absolute neutrophil count	2/19 (10.5%)
BK viruria	2/19 (10.5%)
CMV reactivation	4/19 (21.1%)
Nervous system disorders
syncope	2/19 (10.5%)
headache	4/19 (21.1%)
Renal and urinary disorders
renal failure	3/19 (15.8%)
Respiratory, thoracic and mediastinal disorders
dyspnea	3/19 (15.8%)
hiccoughs	2/19 (10.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.