Clinical trial NCT02071901: Eltrombopag Olamine in Improving Platelet Recovery in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy
Official title: A Single Arm, Phase II Study of Eltrombopag to Enhance Platelet Count Recovery in Elderly Patients With Acute Myeloid Leukemia Undergoing Remission Induction Therapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Secondary Acute Myeloid Leukemia
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2014-02-26
Enrollment: 31
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief summary: This phase II trial studies how well eltrombopag olamine works in improving the recovery of platelet counts in older patients with Acute Myeloid Leukemia (AML) undergoing induction (the first treatment given for a disease) chemotherapy. Platelet counts recover more slowly in older patients, leading to risk of complications and the delay of post-remission therapy. Eltrombopag olamine may cause the body to make platelets after chemotherapy.

Detailed description: PRIMARY OBJECTIVES:

I.To determine whether eltrombopag leads to early platelet recovery in older AML patients (≥ 60years) who attain morphologic remission on day 14 (range, day 14-17) bone marrow assessment following remission induction chemotherapy (IC).

SECONDARY OBJECTIVES:

I. To determine the effect of eltrombopag on megakaryopoiesis - median time to reach platelet count ≥50,000 /μL and ≥100,000 /μL, number of days of platelet transfusion, rates of platelet transfusion-independence and the median time to reach platelet transfusion independence.

II. To determine the effect of eltrombopag on the rates of clinically significant bleeding events (CSBE).

III. To determine the effect of eltrombopag on erythropoiesis the median time to red blood cell transfusion independence.

IV. To determine the effect of eltrombopag on granulopoiesis- the time taken to reach an absolute neutrophil count of ≥ 500 /μL. V. To determine the safety and tolerability of eltrombopag in AML patients undergoing remission IC - incidence and severity of eltrombopag-related adverse events. VI. To determine rates of complete remission (CR), rates of partial complete remission (CRp), time to attain CR, and time to initiation of post-remission consolidation therapy.

OUTLINE:

Participants receive eltrombopag olamine orally (PO) once daily (QD) until platelet counts reach ≥50,000/uL or for 8 weeks, whichever comes earlier. Treatment continues in the absence of unacceptable toxicity.

After completion of study treatment, participants are followed up for 2 years.

Eligibility criteria: Inclusion Criteria:

* All categories of AML will be included except for acute promyelocytic leukemia (APL), acute megakaryocytic leukemia, and acute leukemias of ambiguous lineage undergoing 7 + 3 remission IC with cytarabine and an anthracycline (daunorubicin or idarubicin). All cases have to be histopathologically confirmed by a diagnostic bone marrow biopsy. Use of granulocyte colony-stimulating factor (G-CSF) for any indication must have been discontinued at least 7 days prior to entry into the study.
* Patients with secondary AML arising out of Myelodysplastic syndrome (MDS) (all subtypes under WHO \[World Health Organization\] classification), chronic myelomonocytic leukemia (CMML); therapy-related AML and those with a prior autologous hematopoietic cell transplantation are eligible.
* No morphological evidence of disease on day 14 bone marrow examination following IC
* Must be able to give voluntary informed written consent to participate in the study; informed consent will be obtained prior to initiation of remission IC and before any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
* Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below:

  1. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation.
  2. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study or to abstain.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent
* Any active malignancy (unrelated, non-hematological malignancy) diagnosed within the past 12 months of starting the study drug (other than curatively treated carcinoma-in-situ of the cervix or non-melanoma skin cancer).
* Secondary AML arising out of myeloproliferative neoplasms \[as per the revised 2008 WHO classification of myeloid neoplasms and acute leukemias\] and MDS/myeloproliferative disease (MPD) neoplasms other than CMML \[as per the revised 2008 WHO classification of myeloid neoplasms and acute leukemias\]. Refractory Anemia with Ringed Sideroblasts with thrombocytosis (RARS-T) classified as MDS/MPN neoplasm, unclassifiable will be excluded. AML patients with presenting features suspicious of underlying unrecognized MPD such as marked splenomegaly (\> 20 cm) and thrombocytosis (\>400,000 per microliter) will be excluded. Patients with relapsed or refractory AML will be excluded.
* Radiation therapy, cytotoxic chemotherapy, and combined modality (both radiation and chemotherapy) used to treat other cancers or medical conditions and administered within 12 months prior to signing informed consent. Use of hydroxyurea or emergent leukapheresis (for cytoreduction of highly elevated white blood cell counts) is permissible. Those AML patients who initially receive treatment with all-trans retinoic acid (ATRA) for presumptive diagnosis of APL but if APL is ruled out in final pathology will be eligible for the study.
* Prior history of treatment with recombinant thrombopoietin (TPO) or TPO-receptor (R) agonists
* History of arterial or venous thrombosis \[excluding line-thrombosis\] within the last 1 year, or those with known inherited coagulopathies. Arterial or venous thrombosis includes pulmonary embolism, deep vein thrombosis of both upper \[excluding line-thrombosis\] and lower extremities, coronary artery disease managed medically or requiring intervention (percutaneous stent placement or coronary bypass surgery), cerebrovascular accident (for transient ischemic attacks clinical documentation is required), or involvement of other organs (such as hepatic, renal, spleen or other sites).
* Evidence of fibrosis on bone marrow examination at the time of diagnosis
* Active participation in any other investigational treatment study
* Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, symptomatic congestive heart failure, cardiac arrhythmia, unstable angina or renal insufficiency (acute or chronic) on hemodialysis
* Liver enzymes (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) can not be greater than or equal to 2.5 times the upper limits of normal (ULN)
* Total bilirubin ≥ 1.5 x ULN within 14 days of enrollment.
* Serum creatinine should be ≥ 2.5 x ULN within 14 days of enrollment
* A known immediate or delayed hypersensitivity reaction or idiosyncrasy that, in the opinion of the Medical Monitor is due to drugs chemically related to eltrombopag or excipients (e.g. mannitol)
* Known history of human immunodeficiency virus (HIV) or active hepatitis B or C
* No major surgery within 2 weeks prior to trial enrollment
* Female subject is pregnant or breast-feeding
* Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy while receiving study treatment.

Primary outcomes:
measure: Number of Participants With a Median Platelet Count >= 50,000/uL
timeFrame: Day 24 of Treatment
Secondary outcomes:
measure: Median Time Needed to Reach Platelet Count >= 50,000 /µL in Days
timeFrame: up to 12 weeks
measure: Median Days of Platelet Transfusions
timeFrame: Up to 12 weeks
measure: Rates of Clinically Significant Bleeding Events
timeFrame: Up to 12 weeks
measure: Median Time to Absolute Neutrophil Recovery, Defined as > 500/uL
timeFrame: Up to 12 weeks
measure: Median Rise in Hemoglobin Level in Patients With Pretreatment Hemoglobin of < 8 g/dL
timeFrame: Up to 12 weeks
measure: Complete Response Rate
timeFrame: Up to 12 weeks
measure: Median Days to Attain Complete Response
timeFrame: Up to 12 weeks
measure: Partial Complete Response Rate
timeFrame: Up to 12 weeks
measure: Time to Initiation of Post-remission Therapy
timeFrame: Up to 12 weeks
measure: Rate of Refractory or Persistent Disease
timeFrame: Up to 12 weeks
measure: Overall Survival (OS) - Percent of Participants Alive at Follow-up
timeFrame: at 28 days, at 6 months and up to 5 years
measure: Number of Participants With 3/4 Adverse Events Adverse Events, Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
timeFrame: Up to 4 weeks after last dose of eltrombopag olamine
measure: Disease-Free Survival
timeFrame: At 5 year follow-up
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Case Comprehensive Cancer Center
name: Sudipto Mukherjee, MD, PhD, MPH
role: PRINCIPAL_INVESTIGATOR
References: