Clinical trial NCT00804856: Phase I/IIa Trial to Investigate BI 6727 (Volasertib) as Monotherapy or in Combination With Cytarabine in Acute Myeloid Leukaemia
Official title: An Open Phase I/IIa Trial to Investigate the Maximum Tolerated Dose, Safety, Pharmacokinetics, and Efficacy of Intravenous BI 6727 as Monotherapy or in Combination With Subcutaneous Cytarabine in Patients With Acute Myeloid Leukaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-12-09
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The trial will be performed in two parts, a phase I part and a phase IIa part. In the phase I part of the trial, BI 6727 will be investigated as monotherapy and in combination with low dose cytarabine (LD-Ara-C) in patients with relapsed/refractory AML that are not eligible for intensive treatment. The dose of BI 6727 will be escalated to determine the maximum tolerated dose (MTD) of BI 6727 monotherapy and BI 6727 in combination with LD-Ara-C in AML patients. In the phase IIa part, the combination of BI 6727 at MTD with LD-Ara-C and LD-Ara-C monotherapy will be investigated to explore the efficacy of the combination schedule in comparison to LD-Ara-C monotherapy in previously untreated AML patients that are not eligible for intensive treatment.


Eligibility criteria: Inclusion criteria:

Male or female adult with relapsed/refractory AML ineligible for intensive treatment (phase I part only) Male or female adult with previously untreated AML ineligible for intensive treatment (phase IIa part only) Confirmed diagnosis of AML according to the WHO definition (except for acute promyelocytic leukaemia, APL) Patient is eligible for LD-Ara-C treatment Life expectancy \> 3 months Eastern co-operative oncology group (ECOG, R01-0787) performance score \<=2 at screening Signed written informed consent consistent with international conference on harmonisation, good clinical practice (ICH-GCP) and local legislation

Exclusion criteria:

Previously untreated AML (phase I part only) Relapsed or treatment refractory AML (phase IIa part only) Patient with APL (AML subtype M3 according to the French-American-British (FAB) classification) Hypersensitivity to one of the trial drugs or the excipients Other malignancy requiring treatment Symptomatic central nervous system involvement Clinically relevant QT prolongation (e.g. long QT syndrome, QTcF\>470 ms) 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 in case of known leukaemia liver involvement Prothrombin time (PT) \> 1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin) Bilirubin greater than 1.5 mg/dl (\> 26 mcmol/L) Serum creatinine greater than 2.0 mg/dl Concomitant intercurrent illness, which would compromise the evaluation of efficacy or safety of the trial drug, e.g. active severe infection, unstable angina pectoris, cardiac arrhythmia or severe heart failure/cardiac insufficiency.

Psychiatric illness or social situation that would limit compliance with trial requirements Concomitant therapy, which is considered relevant for the evaluation of the efficacy or safety of the trial drug Contraindications for cytarabine treatment according to the SPC Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial, i.e. combination of two forms of effective contraception (hormonal contraception, intrauterine device, condom with spermicide, etc.).

Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial Pregnant or nursing female patients Patient unable to comply with the protocol

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose (MTD) of Volasertib in Combination With LDAC (Schedule A) and Volasertib Monotherapy (Schedule B)
timeFrame: First Treatment cycle, up to 28 days.
measure: Phase II: Number of Patients With Objective Response (Complete Remission (CR) + Complete Remission With Incomplete Blood Count Recovery (CRi))
timeFrame: The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 869 days.
measure: Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
timeFrame: First Treatment cycle, up to 28 days.
Secondary outcomes:
measure: Best Overall Response
timeFrame: The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 869 days.
measure: Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi)
timeFrame: The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 594 days.
measure: Phase II: Event Free Survival
timeFrame: The patients that entered the trial, and measured from the date of randomization to the date of disease progression (treatment failure), relapse or death from any cause, whichever occurred first, up to 1000 days..
measure: Phase II: Overall Survival
timeFrame: The patients that entered the trial, and measured from the date of randomisation until death from any cause, up to 1100 days..
measure: Phase II: Relapse - Free Survival
timeFrame: The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence or death from any cause, whichever occurred first, up to 900 days.
measure: Phase II: Remission Duration
timeFrame: The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse), up to 900 days.
measure: Phase II: Time to Remission
timeFrame: The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse), up to 158 days.
measure: Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment
timeFrame: Baseline and End of Treatment (up to 869 days).
measure: Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib
timeFrame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration.
measure: Apparent Volume of Distribution of Volasertib at Steady State (VSS)
timeFrame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration.
measure: Dose Normalized Maximum Measured Concentration of Cytarabine in Plasma (Cmax, Norm)
timeFrame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration.
measure: Dose Normalized Area Under the Concentration-Time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated up to 4 Hours
timeFrame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h after first drug administration.
measure: Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals
timeFrame: Baseline (Days -14 to -1) and day 1 (1 hour and 24 hours) after start of infusion.
measure: QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1
timeFrame: Baseline (Days -14 to -1) and day 1 (1 hour and 24 hours) after start of infusion.
measure: Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1
timeFrame: First treatment cycle, up to 28 days.
measure: Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1
timeFrame: First treatment cycle, up to 28 days.
measure: Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles
timeFrame: From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 615 days.
measure: Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles
timeFrame: From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 597 days.
measure: Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles
timeFrame: From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 890 days.
Other outcomes:
Locations:
city: Graz
country: Austria
facility: LKH-Univ. Hospital Graz
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge
city: Bruxelles
country: Belgium
facility: Brussels - UNIV Saint-Luc
city: Leuven
country: Belgium
facility: UZ Leuven
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Montreal General Hospital - McGill University Health Centre
state: Quebec
city: Sherbrooke
country: Canada
facility: CHUS Fleurimont
state: Quebec
city: Caen
country: France
facility: HOP Clémenceau, Hémato, Caen
city: Cergy Pontoise Cedex
country: France
facility: HOP, Centre Hospitalier René Dubos, Hémato, Paris
city: Limoges
country: France
facility: HOP Dupuytren 1
city: Lyon Cedex 03
country: France
facility: HOP Edouard Herriot
city: Nice Cedex 2
country: France
facility: CTR, fondation Paschetta, Hémato, Nice
city: Paris cedex 10
country: France
facility: HOP Saint-Louis
city: Rouen Cedex
country: France
facility: CTR Henri Becquerel
city: Berlin
country: Germany
facility: Campus Virchow-Klinikum, Berlin
city: Frankfurt/Main
country: Germany
facility: Universitätsklinikum Frankfurt
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Kiel
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Brescia
country: Italy
facility: A.O. Spedali Civili di Brescia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Modena
country: Italy
facility: Azienda Ospedaliera Policlinico di Modena
city: Bergen
country: Norway
facility: Haukeland Universitetssykehus
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF, Ullevål sykehus
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Dohner H, Lubbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Muller-Tidow C, Kramer A, Raffoux E, Dohner K, Schlenk RF, Voss F, Taube T, Fritsch H, Maertens J. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood. 2014 Aug 28;124(9):1426-33. doi: 10.1182/blood-2014-03-560557. Epub 2014 Jul 8.