Phase I/IIa Trial to Investigate BI 6727 (Volasertib) as Monotherapy or in Combination With Cytarabine in Acute Myeloid Leukaemia

NCT00804856 | Completed Phase 2 Results

• 2 other identifiers: 1230.42008-003617-27
• Study Type: interventional
• Target: 180
• Locations: 7 countries
• Sites: 27

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.

Conditions

Leukemia, Myeloid, Acute

Outcome Measures

Primary Outcomes (3)

• Phase I: Maximum Tolerated Dose (MTD) of Volasertib in Combination With LDAC (Schedule A) and Volasertib Monotherapy (Schedule B)

  To determine the Maximum tolerated dose (MTD), dose escalation was conducted following the 3+3 design with de-escalation. The MTD was defined as the highest dose at which 6 patients had been treated and less than 2 patients experienced a Dose limiting toxicity (DLT) within the first cycle of treatment. The MTD was defined based on safety data from the first cycle only. DLT is defined as drug related Common terminology criteria for adverse events (CTCAE) grade ≥ 3 nonhaematological toxicity (excluding: untreated nausea, untreated vomiting, CTCAE grade 3 untreated diarrhoea, CTCAE grade 3 "febrile neutropenia" and CTCAE grade 3 "infection with grade 3 or 4 neutrophils"). In patients with complete remission with incomplete blood count recovery (CRi) or partial remission (PR), persistent CTCAE grade 4 neutropenia or thrombocytopenia until three weeks after the end of the treatment cycle will be regarded a DLT.

  First Treatment cycle, up to 28 days.

• Phase II: Number of Patients With Objective Response (Complete Remission (CR) + Complete Remission With Incomplete Blood Count Recovery (CRi))

  Phase II: Number of patients with Objective Response (Complete remission (CR) + Complete remission with incomplete blood count recovery (CRi)). Complete remission (CR): morphologically leukaemia-free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no Auer rods, no evidence of extramedullary leukaemia) and absolute neutrophil count ≥1,000/microliter (μL) and platelets \>100,000/μL. Complete remission with incomplete blood count recovery ("incomplete" CR, CRi): all of the above criteria for CR were met except that neutrophils \<1,000/μL or platelets \<100,000/μL in the blood were not achieved.

  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.

• Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)

  A DLT was defined as a drug related CTCAE (Common Toxicity Criteria for Adverse Events) Grade ≥3 non-haematological toxicity (excluding untreated nausea, untreated vomiting, Grade 3 untreated diarrhea, Grade 3 febrile neutropenia, and Grade 3 infection with Grade 3 or 4 neutrophils). In patients with CRi (Complete Remission with Incomplete Blood Count Recovery) or PR (Partial Remission), persistent Grade 4 neutropenia or thrombocytopenia for 3 weeks after the end of the treatment cycle was regarded as a DLT unless the respective Grade 4 cytopenia was preexistent. In patients who required platelet substitution to maintain a Grade \<4 before treatment, a Grade 4 thrombocytopenia after treatment did not constitute a DLT.

  First Treatment cycle, up to 28 days.

Secondary Outcomes (19)

• Best Overall Response

  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.

• Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi)

  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.

• Phase II: Event Free Survival

  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..

• Phase II: Overall Survival

  The patients that entered the trial, and measured from the date of randomisation until death from any cause, up to 1100 days..

• Phase II: Relapse - Free Survival

  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.

Study Arms (15)

Phase I Schedule A. Volasertib 150 mg+LDAC

EXPERIMENTAL

Volasertib 150 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Phase I Schedule A. Volasertib 200 mg+LDAC

EXPERIMENTAL

Volasertib 200 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Phase I Schedule A. Volasertib 250 mg+LDAC

EXPERIMENTAL

Volasertib 250 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Phase I Schedule A. Volasertib 300 mg+LDAC

EXPERIMENTAL

Volasertib 300 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Phase I Schedule A. Volasertib 350 mg+LDAC

EXPERIMENTAL

Volasertib 350 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Phase I Schedule A. Volasertib 400 mg+LDAC

EXPERIMENTAL

Volasertib 400 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Phase I Schedule B. Volasertib 150 mg

EXPERIMENTAL

Volasertib 150 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase I Schedule B. Volasertib 200 mg

EXPERIMENTAL

Volasertib 200 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase I Schedule B. Volasertib 350 mg

EXPERIMENTAL

Volasertib 350 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase I Schedule B. Volasertib 400 mg

EXPERIMENTAL

Volasertib 400 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase I Schedule B. Volasertib 450 mg

EXPERIMENTAL

Volasertib 450 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase I Schedule B. Volasertib 500 mg

EXPERIMENTAL

Volasertib 500 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase I Schedule B. Volasertib 550 mg

EXPERIMENTAL

Volasertib 550 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Drug: Volasertib

Phase II Schedule C. LDAC

ACTIVE COMPARATOR

Low-dose cytarabine (LDAC) monotherapy 2x20 milligram (mg) per day administered by subcutaneous injection on days 1-10 of each 28 days treatment cycle.

Drug: Cytarabine

Phase II Schedule A. Volasertib 350 mg+LDAC

EXPERIMENTAL

Volasertib 350 milligram (mg) on Days 1 and 15 (28-day cycle) administered by Intravenous Infusion (IV) over 60 minutes and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 days treatment cycle.

Drug: Volasertib; Drug: Cytarabine

Interventions

Volasertib DRUG

Volasertib administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).

Phase I Schedule A. Volasertib 150 mg+LDAC; Phase I Schedule A. Volasertib 200 mg+LDAC; Phase I Schedule A. Volasertib 250 mg+LDAC; Phase I Schedule A. Volasertib 300 mg+LDAC; Phase I Schedule A. Volasertib 350 mg+LDAC; Phase I Schedule A. Volasertib 400 mg+LDAC; Phase I Schedule B. Volasertib 150 mg; Phase I Schedule B. Volasertib 200 mg; Phase I Schedule B. Volasertib 350 mg; Phase I Schedule B. Volasertib 400 mg; Phase I Schedule B. Volasertib 450 mg; Phase I Schedule B. Volasertib 500 mg; Phase I Schedule B. Volasertib 550 mg; Phase II Schedule A. Volasertib 350 mg+LDAC

Cytarabine DRUG

Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle.

Phase I Schedule A. Volasertib 150 mg+LDAC; Phase I Schedule A. Volasertib 200 mg+LDAC; Phase I Schedule A. Volasertib 250 mg+LDAC; Phase I Schedule A. Volasertib 300 mg+LDAC; Phase I Schedule A. Volasertib 350 mg+LDAC; Phase I Schedule A. Volasertib 400 mg+LDAC; Phase II Schedule A. Volasertib 350 mg+LDAC; Phase II Schedule C. LDAC

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (27)

LKH-Univ. Hospital Graz

Graz, 8036, Austria

Location

AZ Sint-Jan Brugge

Bruges, 8000, Belgium

Location

Brussels - UNIV Saint-Luc

Brussels, 1200, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Montreal General Hospital - McGill University Health Centre

Montreal, Quebec, H3G 1A4, Canada

Location

CHUS Fleurimont

Sherbrooke, Quebec, J1H 5N4, Canada

Location

HOP Clémenceau, Hémato, Caen

Caen, 14033, France

Location

HOP, Centre Hospitalier René Dubos, Hémato, Paris

Cergy-Pontoise, 95303, France

Location

HOP Dupuytren 1

Limoges, 87042, France

Location

HOP Edouard Herriot

Lyon, 69437, France

Location

CTR, fondation Paschetta, Hémato, Nice

Nice, 06189, France

Location

HOP Saint-Louis

Paris, 75475, France

Location

CTR Henri Becquerel

Rouen, 76088, France

Location

Campus Virchow-Klinikum, Berlin

Berlin, 13353, Germany

Location

Universitätsklinikum Frankfurt

Frankfurt am Main, 60590, Germany

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Universitätsklinikum Schleswig-Holstein, Campus Kiel

Kiel, 24116, Germany

Location

Universitätsklinikum Münster

Münster, 48149, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

A.O. Spedali Civili di Brescia

Brescia, 25123, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Azienda Ospedaliera Policlinico di Modena

Modena, 41100, Italy

Location

Haukeland Universitetssykehus

Bergen, N-5021, Norway

Location

Oslo Universitetssykehus HF, Ullevål sykehus

Oslo, N-0450, Norway

Location

Related Publications (1)

• 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.

  PMID: 25006120 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

BI 6727; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

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: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1800-243-0127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2008
• First Posted: December 9, 2008
• Study Start: November 27, 2008
• Primary Completion: March 9, 2012
• Study Completion: April 23, 2021
• Last Updated: October 3, 2023
• Results First Posted: October 3, 2023

Record last verified: 2022-12

Locations

IT (3); NO (2); AU (1); BE (3); CA (3); FR (7); DE (8)