Phase I/II Trial: BIBF 1120 Added to Low-dose Cytarabine in Elderly Patients With Acute Myeloid Leukemia (AML)

A Single-arm, Open Label, Multi-center Phase I/II Trial to Assess the Safety and Efficacy of BIBF 1120 Added to Low-dose Cytarabine in Elderly Patients With AML Unfit for an Intensive Induction Therapy

RATIONALE: Low-dose cytarabine works in a minority of elderly patients with an acute myeloid leukemia unfit for intensive induction therapy by killing of leukemia cells. Addition of BIBF1120 to low-dose cytarabine might enhance the killing of leukemia cells.

PURPOSE: This phase I / II trial is studying how safe BIBF1120 can be combined with low-dose cytarabine (phase I) and how well the combination of low-dose cytarabine and BIBF1120 works in elderly patients with acute myeloid leukemia unfit for intensive chemotherapy (phase II).

Study Overview

• Status: Unknown
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: triple kinase inhibitor BIBF1120

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Münster, Germany, 48149
    • Universitätsklinikum Münster, Medizinische Klinik und Poliklinik A

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with newly diagnosed AML (except APL) according to the FAB or WHO classification, including AML evolving from MDS or other hematological diseases and AML after previous cytotoxic therapy or radiation (secondary AML), with medical contraindications against or not willing to receive a standard induction and consolidation therapy.
• Bone marrow aspirate or biopsy must contain > 20% blasts of all nucleated cells. In AML FAB M6 ≥ 30% of non-erythroid cells in the bone marrow must be leukemic blasts. In patients with 20-30% blasts, the indication for a treatment with hypomethylating agents (5-azacitidine or decitabine) should be considered prior to inclusion into the trial.
• Age ≥ 60 years
• Informed consent, personally signed and dated to participate in the study
• Male patients enrolled in this trial must use adequate barrier birth control measures during the course of treatment and for at least 3 months after the last administration of study therapy (low-dose cytarabine and/or BIBF 1120).

Exclusion Criteria:

• Patients with 20-30% bone marrow blasts which are qualifying for and consenting into a therapy with hypomethylating agents
• Patients who are eligible for and consenting into a standard chemotherapy
• Known central nervous system manifestation of AML
• Inadequate liver function (ALT and AST ≥ 2.5 x ULN) if not caused by leukemic infiltration
• Known chronically active hepatitis C infection or acute hepatitis
• Chronically impaired renal function (creatinin clearance < 30 ml/min)
• Uncontrolled hypertension with a resting pressure systolic > 160 mmHg or diastolic > 95 mmHg despite adequate treatment
• severe trauma or surgery within 4 weeks of study entry
• severe, non-healing wounds, ulcer or fracture
• Uncontrolled active infection
• Concurrent malignancies other than AML or other severe diseases which in the opinion of the investigator are likely to influence the endpoint assessment
• Hypersensitivity to cytarabine (not including drug fever or exanthema)
• Previous treatment of AML except hydroxyurea up to 24 hours before study medication
• Previous therapy with tyrosine kinase inhibitors or angiogenesis inhibitors
• Parallel participation in another clinical trial for the same indication. Eligibility of patients with investigational drug therapy outside of this trial during or within 4 weeks of study entry should be discussed with the study office prior to study entry
• Any severe concomitant condition, which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BIBF 1120	Drug: triple kinase inhibitor BIBF1120; triple kinase inhibitor BIBF1120 is given in addition to low-dose cytarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase I: defining maximum tolerated dose (MTD)	4 weeks
Phase II: overall response rate (ORR)	up to 6 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission (CR) rate		up to 12 month
overall survival (OS)		up to 12 month
relapse-free survival (RFS)of the responding patients		up to 12 month
number of participants with adverse events as a measure of safety and tolerability		up to 12 month
ORR rate of the Flt3-mutated patients versus the Flt3-wildtype patients		up to 12 month
CR rate of the Flt3-mutated patients versus the Flt3-wildtype patients		up to 12 month
OS of the Flt3-mutated patients versus the Flt3-wildtype patients		up to 12 month
time to response (CR, CRp, CRi) of the responding patients	CRp = complete remission with incomplete platelet recovery CRi = complete remission with incomplete neutrophil recovery	up to 12 month

Collaborators and Investigators

• Sponsor: University Hospital Muenster
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Utz Krug, MD, University Hospital Münster, Medizinische Klinik und Poliklinik A

Publications and helpful links

General Publications

• Berdel AF, Koch R, Gerss J, Hentrich M, Peceny R, Bartscht T, Steffen B, Bischoff M, Spiekermann K, Angenendt L, Mikesch JH, Kewitz T, Butterfass-Bahloul T, Serve H, Lenz G, Berdel WE, Krug U, Schliemann C. A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy. Ann Hematol. 2023 Jan;102(1):63-72. doi: 10.1007/s00277-022-05025-0. Epub 2022 Nov 18.
• Schliemann C, Gerss J, Wiebe S, Mikesch JH, Knoblauch N, Sauer T, Angenendt L, Kewitz T, Urban M, Butterfass-Bahloul T, Edemir S, Vehring K, Muller-Tidow C, Berdel WE, Krug U. A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia. PLoS One. 2016 Oct 7;11(10):e0164499. doi: 10.1371/journal.pone.0164499. eCollection 2016.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Anticipated): November 1, 2014

Study Registration Dates

• First Submitted: November 15, 2011
• First Submitted That Met QC Criteria: December 6, 2011
• First Posted (Estimate): December 8, 2011

Study Record Updates

• Last Update Posted (Estimate): December 11, 2013
• Last Update Submitted That Met QC Criteria: December 10, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: UKM10_0014; 2011-001086-41 (EudraCT Number)