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Trial of Eltrombopag During Consolidation Therapy in Adults With AML in Complete Remission (PrE0901)

This study is currently recruiting participants.
Verified April 2013 by PrECOG, LLC.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
PrECOG, LLC.
ClinicalTrials.gov Identifier:
NCT01656252
First received: July 31, 2012
Last updated: April 1, 2013
Last verified: April 2013
History of Changes
  Purpose

Patients with Acute Myeloid Leukemia (AML) in complete remission will receive eltrombopag while undergoing consolidation chemotherapy with high-dose cytarabine. Eltrombopag may help increase the number of platelets during chemotherapy and may help prevent the risk of bleeding.

Phase I will study the side effects, best dose and platelet effects of eltrombopag when given with consolidation chemotherapy. After the maximum safe and tolerated dose and schedule is found in Phase I, the study will proceed to Phase II. Phase II will confirm the dose and schedule of eltrombopag identified in Phase I that can increase platelet counts in patients receiving consolidation therapy.


Condition Intervention Phase
Acute Myeloid Leukemia
 Drug: Phase I- Cytarabine & Eltrombopag
Drug: Phase II- Sequence A
Drug: Phase II- Sequence B
 Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phase I Dose Finding/Phase II Placebo-Controlled Trial of Eltrombopag During Consolidation Therapy in Adults With Acute Myeloid Leukemia (AML) in Complete Remission

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by PrECOG, LLC.:

Primary Outcome Measures:
  • Phase I- Optimal tolerated dose of eltrombopag [ Time Frame: 13 months ] [ Designated as safety issue: Yes ]
    To determine the safety, tolerability and optimal dose of eltrombopag in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy.

  • Phase I- Kinetics of platelet count recovery [ Time Frame: 13 months ] [ Designated as safety issue: No ]
    To describe the kinetics of platelet count recovery in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy who will be receiving eltrombopag.

  • Phase II- Assess if platelet count recovery is increased with eltrombopag [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine if platelet recovery following consolidation chemotherapy is accelerated with eltrombopag.


Secondary Outcome Measures:
  • Phase I & Phase II- Pharmacokinetics of eltrombopag [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine the plasma concentrations of eltrombopag in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy (selected dosing regimen only).

  • Phase II- Platelet transfusion requirements [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine the impact of eltrombopag on platelet transfusion requirements in the setting of consolidation chemotherapy.

  • Phase II- Red blood cell transfusion requirements [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine the impact of eltrombopag on red blood cell transfusion requirements.

  • Phase II- Bleeding event occurrence [ Time Frame: 62 months ] [ Designated as safety issue: Yes ]
    To determine the impact of eltrombopag on occurrence of bleeding events.

  • Phase II- Time to platelet count recovery [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine the impact of eltrombopag on time to platelet recovery following consolidation chemotherapy.

  • Phase II- Depth of platelet nadir [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine the impact of eltrombopag on the depth of platelet nadir following a cycle of consolidation chemotherapy.

  • Phase II- Duration of platelet nadir [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine the duration of platelet nadir in the setting of eltrombopag exposure.

  • Phase II- Safety of eltrombopag with consolidation [ Time Frame: 62 months ] [ Designated as safety issue: Yes ]
    To determine the safety and tolerability of eltrombopag when given at the optimal dose in the setting of consolidation chemotherapy.

  • Exploratory- Eltrombopag effect on TPO/EPO [ Time Frame: 62 months ] [ Designated as safety issue: No ]
    To determine if eltrombopag has an effect on TPO and/or EPO in this setting.


Estimated Enrollment: 90
Study Start Date: July 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I- Cytarabine & Eltrombopag
Cycle 1= Cytarabine twice daily on Days 1, 3 and 5 and Eltrombopag (Open-Label) until platelet recovery or for 35 consecutive days, whichever occurs first. Phase I will determine the dose and schedule of Eltrombopag to be used in Phase II.
 Drug: Phase I- Cytarabine & Eltrombopag

Cycle 1= Cytarabine 3 g/m² IV twice daily on Days 1, 3 and 5 (Patients >60 years of age will receive cytarabine 1.5 g/m² IV per dose). Day 1 must start in AM.

Eltrombopag (Open-Label) by mouth daily until platelet recovery or for 35 consecutive days, whichever occurs first. Phase I will determine the dose and schedule of Eltrombopag to be used in Phase II.

One cycle of consolidation therapy with high-dose cytarabine and eltrombopag will be received on study. Additional chemotherapy may be administered at the investigators discretion without eltrombopag.

Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • Promacta
  • Thrombopoietic Agent
Experimental: Phase II- Sequence A
Cytarabine twice daily on Days 1, 3 and 5. Eltrombopag(dose and schedule as determined in Phase I) with 1st cycle of high-dose consolidation chemotherapy and placebo with 2nd cycle. Treatment sequence will be blinded to the patient and all study/sponsor personnel.
 Drug: Phase II- Sequence A

Cytarabine 3 g/m² IV twice daily on Days 1, 3 and 5 (Patients >60 years of age will receive cytarabine 1.5 g/m² IV per dose). Day 1 must start in AM.

Eltrombopag by mouth daily (dose and schedule as determined in Phase I) with 1st cycle of high-dose consolidation chemotherapy and placebo by mouth daily with 2nd cycle.

Eltrombopag/placebo will continue until platelet recovery or for 35 consecutive days, whichever occurs first.

Additional chemotherapy may be administered at the investigators discretion without eltrombopag.

Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • Promacta
  • Thrombopoietic Agent
Experimental: Phase II- Sequence B
Cytarabine twice daily on Days 1, 3 and 5. Placebo with 1st cycle of high-dose consolidation therapy and Eltrombopag(dose and schedule as determined in Phase I) with 2nd cycle. Treatment sequence will be blinded to the patient and all study/sponsor personnel.
 Drug: Phase II- Sequence B

Cytarabine 3 g/m² IV twice daily on Days 1, 3 and 5 (Patients >60 years of age will receive cytarabine 1.5 g/m² IV per dose). Day 1 must start in AM.

Placebo by mouth daily with 1st cycle of high-dose consolidation therapy and Eltrombopag by mouth daily (dose and schedule as determined in Phase I) with 2nd cycle.

Eltrombopag/placebo will continue until platelet recovery or for 35 consecutive days, whichever occurs first.

Additional chemotherapy may be administered at the investigators discretion without eltrombopag.

Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • Promacta
  • Thrombopoietic Agent

Detailed Description:

Consolidation chemotherapy with high dose cytarabine usually causes myelosuppression for 14 to 21 days after each treatment. Patients have low blood counts for days or weeks before the bone marrow resumes function. This may result in e.g., hospitalization, treatment with antibiotics, and transfusions with blood and/or platelets. In addition, this may cause a delay in treatment and reduction in dose. To achieve the best outcome from treatment, dose reductions and delays in treatment must be avoided.

The incidence and duration of decreased white blood cells (neutropenia) and neutropenic complications have been reduced by the use of growth colony stimulating factors. Additionally, the use of erythropoietin-stimulating factors has reduced anemia and the need for red blood cell transfusions. Thrombocytopenia remains an important limiting factor in administration of chemotherapy and maintaining dose intensity in some patients. Additionally, the risk of bleeding secondary to low platelet counts may increase sickness or even death in patients undergoing cancer treatment.

Thrombopoietin (TPO) is the principal cytokine involved in the regulation of megakaryopoiesis and platelet production. Eltrombopag is an orally bioavailable, small molecule, TPO-receptor agonist that stimulates platelet production by a similar, but not identical, mechanism to endogenous TPO. Eltrombopag has been approved in the U.S. for the treatment of chronic Idiopathic Thrombocytopenic Purpura. Eltrombopag is also under development for other indications such as Hepatitis C Virus-associated thrombocytopenia, Myelodysplastic Syndrome/AML, and oncology related thrombocytopenias. This agent appears to possess many of the desirable properties for a treatment for chemotherapy induced thrombocytopenia, including oral administration.

The Phase I portion of this study will be conducted using a dose escalation/de-escalation strategy for patients in either the first or second complete remission. Dose escalations are planned in the form of both acceleration of date of initiation of eltrombopag relative to the start of consolidation chemotherapy as well as increasing daily dosing.

The Phase II portion will be conducted using the dose and schedule selected from the Phase I portion of the study for those patients in first complete remission. Patients will be used as their own controls, e.g., a two-period two-treatment cross-over design. Patients will be randomly allocated 1:1 to one of two sequences. Patients randomized to Sequence A will receive eltrombopag with their first cycle of consolidation and placebo with Cycle 2. Patients randomized to Sequence B will receive placebo with their first cycle of consolidation and eltrombopag with Cycle 2. The treatment assignment will be blinded to the patient and all study/sponsor personnel.

Patients will undergo blood sample collection for Thrombopoietin(TPO)/ Erythropoietin(EPO) and pharmacokinetic analysis of eltrombopag in Phase I and pharmacokinetic analysis of eltrombopag in the Phase II portion of the study.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

• Cytomorphologically documented diagnosis of acute myeloid leukemia (AML). Acute promyelocytic leukemia patients will be excluded (FAB M3). FAB classification and cytogenetics must be noted at registration for each subject. For centers that do not use FAB, a special review will be required.

Phase I Enrollment:

  • Must be in first or second complete remission, e.g., no evidence of active disease in blood, bone marrow (<5% blasts), or other tissues.
  • For each remission, may have received no more than 2 cycles of induction treatment (any type).
  • May have received no more than one course of consolidation for the current remission prior to enrollment (any type)

Phase II Enrollment:

  • Must be in first complete remission, e.g., no evidence of active disease in blood, bone marrow (<5% blasts), or other tissues.
  • May have received no more than 2 cycles of induction treatment (any type).

Enrollment in Either Phase:

  • Remission status must be documented by a bone marrow examination up to 14 days prior to study registration.
  • Have recovered from induction and first consolidation (if applicable) therapy side effects (or ≤grade 1).
  • ≥18 years of age and ≤65 years of age.
  • ECOG performance status 0, 1, 2.
  • Have not received cytotoxic drug therapy within 21 days of registration.
  • Have not received hematopoietic colony stimulating growth factors within 14 days of registration.
  • Have not received packed red blood cells or platelets within 7 days of registration.
  • Have not received investigational agents within 30 days of registration and will not receive any investigational agents other than eltrombopag/placebo during study.
  • Signed IRB-approved informed consent.
  • Willing to provide blood samples for research purposes.

  • Adequate organ function obtained within 28 days prior to registration:

    • Absolute neutrophil count >1 x 10⁹/L
    • Platelet count >100 x 10⁹/L
    • Total direct serum bilirubin ≤1.5x upper limit of normal (ULN)
    • ALT and AST ≤3x ULN
    • BUN and serum creatinine <2x ULN
    • Albumin ≥2.5 g/dL
    • PT and PTT 80-120% of institutional normal range
  • Women of childbearing potential must have a negative serum pregnancy test within 14 days of registration.
  • Not pregnant nor breast feeding.
  • Women of childbearing potential and sexually active males must use an accepted and effective method of contraception.
  • Patients of known East Asian ancestry (Chinese, Japanese, Taiwanese, and Korean) are excluded from protocol participation for safety and efficacy reasons.
  • Able to swallow and retain orally administered medication.
  • No clinically significant gastrointestinal abnormalities such as malabsorption syndrome or major resection of the stomach or bowels.
  • No clinical evidence of hepatomegaly or splenomegaly.
  • No known risk for Torsades de Pointes. (Eltrombopag use has not been shown to be associated with Torsades de Pointes.)
  • No active or unresolved infection and must be off all antibiotics for at least 7 days prior to registration.
  • No current evidence of invasive fungal infection.
  • No known Hepatitis B, Hepatitis C active disease.
  • No known Human Immunodeficiency Virus (HIV) seropositivity. The risk for potential toxicities secondary to HIV (e.g., increased risk for fatal opportunistic infection) may confound the toxicity profile of eltrombopag.
  • Patients with a history of Central Nervous System (CNS) leukemia are eligible if there is documentation of no current CNS involvement on cerebrospinal fluid (CSF) examination (e.g., negative CSF by lumbar puncture) within 28 days of registration.
  • No prior or concomitant malignancy in the past 5 years which is currently active and likely to interfere with the patient's treatment for AML or which is likely to increase the patient's morbidity or mortality. No prior chemotherapy or radiation therapy allowed (unless related to AML treatment).
  • No concurrent organ damage or medical problems that would prohibit therapy.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01656252

Contacts
Contact: Kelly Walker, RN 215-789-3634 kwalker@precogllc.org
Contact: Toni Bjurstrom, RN 215-298-2389 tbjurstrom@precogllc.org

Locations
United States, Ohio
University Hospitals Case Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Nancy Horvath, RN, BSN     216-286-2292     nancy.horvath@uhhospitals.org    
Contact: Donna Kane, RN, MSN     216-844-8123     donna.kane1@uhhospitals.org    
Principal Investigator: Hillard Lazarus, MD            
United States, Pennsylvania
Penn State Hershey Cancer Institute Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Brian Couch, RN, CCRP     717-531-0003 ext 285861     bcouch@hmc.psu.edu    
Principal Investigator: Witold Rybka, MD            
Abramson Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Kim Hummel     215-349-5201     Kim.hummel@uphs.upenn.edu    
Contact: Patricia Williams, RN, OCN     215-662-2870     Patricia.williams3@uphs.upenn.edu    
Principal Investigator: Noelle Frey, MD            
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Jessica Piggee, RN     615-875-6120     jessica.l.piggee@vanderbilt.edu    
Principal Investigator: Stephen Strickland, MD            
Sponsors and Collaborators
PrECOG, LLC.
GlaxoSmithKline
Investigators
Study Chair: Hillard M Lazarus, MD University Hospital Case Medical Center
  More Information

Publications:

Responsible Party: PrECOG, LLC.
ClinicalTrials.gov Identifier: NCT01656252     History of Changes
Other Study ID Numbers: PrE0901, ELT114465
Study First Received: July 31, 2012
Last Updated: April 1, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by PrECOG, LLC.:
Acute Leukemia
Complete Remission
Consolidation
Consolidation Chemotherapy
Cytarabine
 Eltrombopag
Leukemia
Thrombocytopenia
Thrombopoietin

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
 Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 21, 2013