BI 836858 Dose Escalation in Patients With Refractory or Relapsed Acute Myeloid Leukemia and in Patients With AML in Complete Remission With High Risk to Relapse

Boehringer Ingelheim30 enrolled

Overview

Patients with acute myeloid leukemia who experience a relapse after at least one prior regimen may be enrolled in this trial. In addition, acute myeloid leukemia patients who are in complete remission with high risk to relapse may be eligible for this trial. The trial will examine whether monotherapy with BI 836858 is safe and tolerable at escalating dose levels.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Leukemia, Myeloid, Acute

Interventions

BI 836858DRUG

Monotherapy with BI 836858 administered as intravenous infusion

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. Diagnosis of relapsed or refractory AML with at least one prior treatment for acute myeloid leukemia and patients with diagnosis of acute myeloid leukemia in complete remission with high risk to relapse. 2. Expression of CD33 on more than 30% of bone marrow blasts at screening for patients with refractory or relapsed acute myeloid leukemia is required. CD33 positive expression of bone marrow blasts at the time of initial acute myeloid leukemia diagnosis is sufficient for those patients in complete remission with high risk to relapse. 3. Eastern Cooperative Oncology Group Performance Status 0, 1 or 2 4. Age 18 years or older 5. Written informed consent which is consistent with International Conference on Harmonization, Good Clinical Practice (ICH-GCP) guidelines and local legislation. Exclusion criteria: 1. Patients with acute promyelocytic leukemia according to WHO definition. 2. Patients with refractory or relapsed acute myeloid leukemia \> 5.000 blasts in the peripheral blood. 3. Anti-leukemia therapy within two weeks before first treatment with BI 836858, 4 weeks for biologics. Parallel treatment with Hydroxyurea ia allowed with refractory or relapsed acute myeloid leukemia patients. 4. Allogeneic stem cell transplantation within the last 28 days before first treatment with graft versus host disease requiring more than 20 mg of steroids per day. Steroid dosage must be stable within two weeks prior to start of treatment. 5. Patients who are candidates for allogeneic stem cell transplantation (for patients with refractory or relapsed acute myeloid leukemia). 6. Second malignancy currently requiring active therapy. 7. Symptomatic central nervous system involvement 8. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (ULN), or AST or ALT greater than 5 times the ULN for those with Gilbert syndrome. 9. Prothrombin time (PT) \>1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin) 10. Bilirubin greater than 1.5 mg/dl (\>26 µmol/L) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert syndrome, or hemolysis. 11. Serum creatinine greater than 2.0 mg/dl 12. Known human immunodeficiency virus (HIV) infection or active hepatitis B virus or hepatitis C virus infection. 13. Concomitant intercurrent illness, or any condition which in the opinion of the Investigator, would compromise safe participation in the study, e.g. active severe infection, unstable angina pectoris, new onset of exacerbation of a cardiac arrhythmia 14. Psychiatric illness or social situation that would limit compliance with trial requirements 15. Concomitant therapy, which is considered relevant for the evaluation of the efficacy or safety of the trial drug 16. Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for 6 months after the last administration of BI 836858 17. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second effective method of contraception during the trial and for 6 months after the last administration of BI 836858 18. Pregnant or nursing female patients 19. Treatment with another investigational agent under the following conditions: 1. Within two weeks (4 weeks for biologics or 5 half-lives, whichever is longer) of first administration of BI 836858; or 2. Patient has persistent toxicities from prior anti-leukemic therapies which are determined to be relevant by the Investigator. 3. Concomitant treatment with another investigational agent while participating in this trial. 20. Prior treatment with a CD33 antibody 21. Patient unable or unwilling to comply with the protocol.

Locations (5)

Northwestern University

Chicago, Illinois, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Washington University School of Medicine

St Louis, Missouri, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Outcomes

Primary Outcomes

Determination of the Maximum Tolerated Dose (MTD) of BI 836858

This trial was discontinued prior to reaching the primary endpoint of determining MTD.

Time frame: From the first administration of BI 836858 to start of the fifth administration, excluding the day of fifth administration, up to 28 days.

Number of Patients With Dose Limiting Toxicity (DLT) During MTD Evaluation

Dose limiting toxicity was defined as any non-disease-related, non-hematological Adverse Events (AE) of Common Terminology Criteria for AE (CTCAE) grade 3 or higher. Number of patients with DLT during the MTD evaluation period for evaluation for patients with refractory or relapsed acute myeloid leukemia, the first 2 cycles (i.e. patient received at least 4 administrations of BI 836858 and reached end of Cycle 2) and for AML patients in CR with high risk to relapse, the first 2 cycles (i.e. patient has received at least 2 administrations of BI 836858 and reached end of Cycle 2).

Time frame: From the first administration of BI 836858 to start of the fifth administration, excluding the day of fifth administration, up to 28 days.

Secondary Outcomes

Best Overall Response According to International Working Group (IWG) Criteria Categorized as CompleteRemission(CR), CR With Incomplete Blood Recovery (CRi), PartialRemission (PR), TreatmentFailure (TF) and ProgressiveDisease (PD)

BOR for patients with refractory/relapsed acute myeloid leukemia defined as: -CR:Morphologically leukemia free state/absolute neutrophil count≥1000/microliter(μL)and platelets≥100,000/μL. No transfusion for 1week prior to assessment -CRi:Met criteria for CR, except absolute neutrophils\<1000/μl/platelets\<100,000/μl -PR:Met criteria for CR, except leukemic blasts in bone marrow may range from 5 to 25% as long as count has decreased by at least 50% from pre-study treatment, or\<5% blasts in presence of Auer rods or abnormal morphology -TF:Patient survives≥7 days following completion of initial 2 treatment cycles with persistent leukemia in the last peripheral blood smear or bone marrow or with persistent extramedullary disease - PD:Patient survives\>7 days following completion of initial 2 treatment cycles with increase of blast population in bone marrow or peripheral blood by\>50% or aggravation or new development of extramedullary disease or further deterioration or death due to leukemia

Data from ClinicalTrials.gov

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The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Time frame: From first administration of study drug until the earliest of progressive disease (PD), death or last adequate disease assessment before new anti-cancer therapy, up to 299 days.

Progression Free Survival for Patients With Refractory or Relapsed Acute Myeloid Leukemia

Progression-free survival was defined as the time from first treatment with BI 836858 until disease progression, relapse or death.

Time frame: From first administration of study drug until progressed according to disease assessment, relapse, or death without progression, up to 167 days.

Time to Treatment Failure for Patients With Refractory or Relapsed Acute Myeloid Leukemia

Time to treatment was defined as the time from first treatment with BI 836858 until disease progression, relapse or death or start of next AML therapy.

Time frame: From first administration of study drug until progressive disease, relapse, death or start of next anti-AML therapy, up to 167 days.

Progression Free Survival for AML Patients in CR With High Risk to Relapse

Progression-free survival was defined as the time from first treatment with BI 836858 until disease progression, relapse or death for AML patients in CR with high risk to relapse.

Time frame: From first treatment with study drug until disease progression, relapse or death for AML patients in CR with high risk to relapse, up to 409 days.

Time to Treatment Failure for AML Patients in CR With High Risk to Relapse

Time to treatment was defined as the time from first treatment with BI 836858 until disease progression, relapse or death or start of next AML therapy.

Time frame: From first treatment with study drug until disease progression, relapse, death or start of next AML therapy for AML patients in CR with high risk to relapse, up to 409 days.

Maximum Measured Plasma Concentration (Cmax)

Maximum measured plasma concentration (Cmax) after the first infusion is presented.

Time frame: At 5 minutes (min) before start of BI 836858 infusion and at 5 hours (hrs), 6 hrs, 9 hrs, 24 hrs and 72 hrs after BI 836858 infusion.

Time From Dosing to the Maximum Plasma Concentration (Tmax)

Time from dosing to the maximum plasma concentration (tmax) after the first infusion is presented.

Time frame: At 5 minutes (min) before start of BI 836858 infusion and at 5 hours (hrs), 6 hrs, 9 hrs, 24 hrs and 72 hrs after BI 836858 infusion.

Area Under the Plasma Concentration-time Curve Over the Time Interval of One Week (AUC0-168)

Area under the plasma concentration-time curve over the time interval of one week (AUC0-168) after the first infusion is presented.

Time frame: At 5 minutes (min) before start of BI 836858 infusion and at 5 hours (hrs), 6 hrs, 9 hrs, 24 hrs, 72 hrs and 168 hrs after BI 836858 infusion.

Area Under the Plasma Concentration-time Curve Over the Time Interval of One Treatment Cycle (AUC0-tz)

Area under the plasma concentration-time curve over the time interval of one treatment cycle (AUC0-tz) is presented. One treatment cycle included a first and a second infusion.

Time frame: At approximately 5 minutes (min) before start of first (Day 1) and second (Day 8) BI 836858 infusion and at 5 hours (hrs), 6 hrs, 9 hrs, 24 hrs, 72 hrs and 168 hrs after first and second BI 836858 infusion.

Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC0-infinity)

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC0-infinity) is presented.