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

NCT01656252 | Terminated Phase 1 Results DMC

• 2 other identifiers: PrE0901ELT114465
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Keywords

Acute Leukemia; Complete Remission; Consolidation; Consolidation Chemotherapy; Cytarabine; Eltrombopag; Leukemia; Thrombocytopenia; Thrombopoietin

Outcome Measures

Primary Outcomes (3)

• Phase I- Optimal Tolerated Dose of Eltrombopag

  To determine the safety, tolerability and optimal dose of eltrombopag in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy. The optimal dose was based on rules involving observation of Dose Limiting Toxicity (DLT events), defined as a CTCAE Version 4 non-hematologic adverse event of grade 3 or higher occurring within 30 days of the last dose of eltrombopag judged by the investigator to be at least possibly related to eltrombopag administration.

  13 months

• Phase I - Dose Level With Best Kinetics of Platelet Count Recovery

  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. This is assessed graphically by plotting platelet count vs. days relative to start of cytarabine for each patient.

  13 months

• Phase II- Assess if Platelet Count Recovery is Increased With Eltrombopag

  To determine if platelet recovery following consolidation chemotherapy is accelerated with eltrombopag.

  62 months

Secondary Outcomes (8)

• Phase I & Phase II- Pharmacokinetics of Eltrombopag

  62 months

• Phase II- Platelet Transfusion Requirements

  62 months

• Phase II- Red Blood Cell Transfusion Requirements

  62 months

• Phase II- Bleeding Event Occurrence

  62 months

• Phase II- Time to Platelet Count Recovery

  62 months

Other Outcomes (1)

• Exploratory- Eltrombopag Effect on TPO/EPO

  62 months

Study Arms (3)

Phase I- Cytarabine & Eltrombopag

EXPERIMENTAL

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

Phase II- Sequence A

EXPERIMENTAL

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

Phase II- Sequence B

EXPERIMENTAL

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

Interventions

Phase I- Cytarabine & Eltrombopag DRUG

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.

Also known as: Ara-C, Cytosar-U, Cytosine Arabinoside, Promacta, Thrombopoietic Agent

Phase I- Cytarabine & Eltrombopag

Phase II- Sequence A DRUG

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.

Also known as: Ara-C, Cytosar-U, Cytosine Arabinoside, Promacta, Thrombopoietic Agent

Phase II- Sequence A

Phase II- Sequence B DRUG

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.

Also known as: Ara-C, Cytosar-U, Cytosine Arabinoside, Promacta, Thrombopoietic Agent

Phase II- Sequence B

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cytomorphologically documented diagnosis of acute myeloid leukemia (AML). Acute promyelocytic leukemia patients will be excluded (FAB M3). FAB classification, cytogenetics and molecular markers (if applicable) must be available at registration.
• 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 28 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 ≤70 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.

Sponsors & Collaborators

• PrECOG, LLC.: lead
• GlaxoSmithKline: collaborator
• Novartis: collaborator

Study Sites (5)

University of Massachusetts Worcester

Worcester, Massachusetts, 01655, United States

Location

Mayo Clinic, Rochester

Rochester, Minnesota, 55905, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Penn State Hershey Cancer Institute

Hershey, Pennsylvania, 17033, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (5)

• Mavroudi I, Pyrovolaki K, Pavlaki K, Kozana A, Psyllaki M, Kalpadakis C, Pontikoglou C, Papadaki HA. Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic syndrome. Leuk Res. 2011 Mar;35(3):323-8. doi: 10.1016/j.leukres.2010.06.029. Epub 2010 Aug 4.

  PMID: 20688394 BACKGROUND

• Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009 Oct 29;114(18):3899-908. doi: 10.1182/blood-2009-04-219493. Epub 2009 Aug 26.

  PMID: 19710504 BACKGROUND

• Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C, Mostafa Kamel Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010 Oct;26(10):2339-46. doi: 10.1185/03007995.2010.510051.

  PMID: 20735290 BACKGROUND

• Vadhan-Raj S. Management of chemotherapy-induced thrombocytopenia: current status of thrombopoietic agents. Semin Hematol. 2009 Jan;46(1 Suppl 2):S26-32. doi: 10.1053/j.seminhematol.2008.12.007.

  PMID: 19245931 BACKGROUND

• Strickland SA, Wang XV, Cerny J, Rowe JM, Rybka W, Tallman MS, Litzow M, Lazarus HM. A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: enhanced platelet recovery during consolidation therapy in acute myeloid leukemia. Leuk Lymphoma. 2020 Sep;61(9):2191-2199. doi: 10.1080/10428194.2020.1762878. Epub 2020 May 30.

  PMID: 32476546 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Pathologic Complete Response; Leukemia; Thrombocytopenia; Jacobs syndrome

Interventions

eltrombopag; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Progression; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Blood Platelet Disorders; Cytopenia

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: PrECOG Statistician
• Organization: ECOG-ACRIN Biostatistics Center

jmanola@jimmy.harvard.edu

617-632-3633

Study Officials

• Hillard M Lazarus, MD

  University Hospitals Cleveland Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2012
• First Posted: August 2, 2012
• Study Start: July 1, 2012
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: November 3, 2020
• Results First Posted: June 28, 2017

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)