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Trial of Intensive Chemotherapy With or Without Volasertib in Patients With Newly Diagnosed High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

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ClinicalTrials.gov Identifier: NCT02198482
Recruitment Status : Terminated (development program of study drug volasertib was stopped by Boehringer Ingelheim due to manufacturing problems)
First Posted : July 23, 2014
Last Update Posted : February 28, 2018
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. Hartmut Doehner, University of Ulm

Brief Summary:
Randomized Phase II Trial of Intensive Chemotherapy With or Without Volasertib (BI 6727) in Patients With Newly Diagnosed High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) High-risk Myelodysplastic Syndrome (MDS) Drug: Volasertib Drug: Cytarabine Drug: Daunorubicin Drug: Mitoxantrone Phase 2

Detailed Description:

The trial is a randomized, Phase II, open label multi-center trial in adult patients with newly diagnosed AML or high-risk MDS as defined in the inclusion/exclusion criteria.

An initial safety run-in study will be performed administering intensive induction therapy consisting of daunorubicin and cytarabine with the study drug volasertib administered prior or after chemotherapy, as well as consolidation therapy consisting of intermediate-dose cytarabine with the study drug volasertib administered prior or after chemotherapy. After establishing the volasertib dose, the randomized Phase II portion of the trial will begin:

Patients will be equally randomized to DA (daunorubicin, cytarabine), V-DA (volasertib administered prior to daunorubicin, cytarabine), and DA-V (volasertib administered after daunorubicin, cytarabine). All patients will receive a second induction cycle with reduced daunorubicin and cytarabine doses. Patients refractory to the first induction cycle and patients not achieving a CR/CRi after two induction cycles will be off-study and followed up.

Patients in CR/CRi after induction therapy will proceed to consolidation therapy. Consolidation will be stratified based on the genetic risk profile (according to ELN criteria) and patient-related factors (e.g., age, HCT-CI, comorbidities, patient wish). Patients with a favorable genetic risk profile and those patients considered ineligible for allogeneic HCT will receive repetitive cycles of consolidation according to initial randomization, either MiDAC, V-MiDAC (volasertib administered prior to cytarabine), or MiDAC-V (volasertib administered after cytarabine). All other patients are assigned to allogeneic HCT.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Dose Finding Safety Run-in Phase Followed by a Randomized Phase II Trial of Intensive Chemotherapy With or Without Volasertib (BI 6727) Administered Prior or After Chemotherapy in Patients With Newly Diagnosed High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
Study Start Date : February 2016
Actual Primary Completion Date : November 2016
Actual Study Completion Date : November 2016


Arm Intervention/treatment
Active Comparator: Daunorubicin, Cytarabine (DA)

DA

Induction I:

  • Daunorubicin 60 mg/m² i.v., d 1-3
  • Cytarabine 100 mg/m² cont. i.v., d 1-7

Induction II:

  • Daunorubicin 50 mg/m² i.v. d 1-3
  • Cytarabine 100 mg/m² cont. i.v., d 1-5

Consolidation therapy:

Patients with genetic favourable risk and those patients not eligible for allogeneic HSCT due to comorbidities, high HCT-CI or patient wish will proceed to 3 cycles of age-adapted consolidation therapy with mitoxantrone and intermediate-dose cytarabine (MiDAC).

  • Mitoxantrone Younger adults (18 to 60 yrs): 10 mg/m2 by i.v. on day 1. Elderly patients (>60 yrs): 8 mg/m2 by i.v. infusion on day 1.
  • Intermediate-dose cytarabine:

Younger adults (18 to 60 yrs): 1500 mg/m2 q12h on days 1-3 Elderly patients (>60 yrs): 1000 mg/m2 q12h on days 1-3 An allogeneic HSCT is intended for patients with intermediate I/II and adverse-risk genetics. Optionally, one cycle of consolidation with MiDAC may be given prior to alloHSCT.

Drug: Cytarabine
Other Name: ARA-cell

Drug: Daunorubicin
Other Name: Daunoplastin

Drug: Mitoxantrone
Other Name: Novantron

Experimental: Volasertib, Daunorubicin, Cytarabine

VDA

Induction I

  • Volasertib i.v., d1
  • Daunorubicin 60 mg/m² i.v., d 2-4
  • Cytarabine 100 mg/m² cont. i.v., d 2-8 Induction II
  • Volasertib i.v., d1
  • Daunorubicin 50 mg/m² i.v. d 2-4
  • Cytarabine 100 mg/m² cont. i.v., d 2-6

Consolidation therapy:

Patients with genetic favourable risk and those patients not eligible for allogeneic HSCT will proceed to 3 cycles of age-adapted consolidation therapy with mitoxantrone and intermediate-dose cytarabine in combination with Volasertib (V-MiDAC).

  • Volasertib i.v., d1
  • Mitoxantrone Younger adults (18 to 60 yrs): 10 mg/m2 by i.v. on day 2. Elderly patients (>60 yrs): 8 mg/m2 by i.v. on day 2.
  • Intermediate-dose cytarabine:

Younger adults (18 to 60 yrs): 1500 mg/m2 q12h on days 2-4 Elderly patients (>60 yrs): 1000 mg/m2 q12h on days 2-4 An allogeneic HSCT is intended for patients with intermediate I/II and adverse-risk genetics. Optionally, one cycle of consolidation with V-MiDAC may be given prior to alloHSCT.

Drug: Volasertib
Drug: Cytarabine
Other Name: ARA-cell

Drug: Daunorubicin
Other Name: Daunoplastin

Drug: Mitoxantrone
Other Name: Novantron

Experimental: Daunorubicin, Cytarabine, Volasertib

DAV

Induction I

  • Volasertib i.v., d7
  • Daunorubicin 60 mg/m² i.v., d 1-3
  • Cytarabine 100 mg/m² i.v., d 1-7 Induction II
  • Volasertib i.v., d5
  • Daunorubicin 50 mg/m² i.v. d 1-3
  • Cytarabine 100 mg/m² cont. i.v., d 1-5

Consolidation therapy:

Patients with genetic fav. risk and those patients not eligible for alloHSCT will proceed to 3 cycles of age-adapted consolidation therapy with mitoxantrone and intermediate-dose cytarabine in combination with Volasertib (MiDAC-V).

  • Volasertib i.v., d4
  • Mitoxantrone Younger adults (18 to 60 yrs): 10 mg/m2 by i.v. on day 1. Elderly patients (>60 yrs): 8 mg/m2 by i.v. on day 1.
  • Intermediate-dose cytarabine:

Younger adults (18 to 60 yrs): 1500 mg/m2 q12h on days 1-3 Elderly patients (>60 yrs): 1000 mg/m2 q12h on days 1-3 An allogeneic HSCT is intended for patients with intermediate I/II and adverse-risk genetics. Optionally, one cycle of consolidation with MiDAC-V may be given prior to alloHSCT.

Drug: Volasertib
Drug: Cytarabine
Other Name: ARA-cell

Drug: Daunorubicin
Other Name: Daunoplastin

Drug: Mitoxantrone
Other Name: Novantron




Primary Outcome Measures :
  1. Rate of complete remission (CR) and CR with incomplete blood count recovery (CRi) [ Time Frame: 2 months ]

Secondary Outcome Measures :
  1. Cumulative incidence of relapse [ Time Frame: 4 years ]
  2. Cumulative incidence of death [ Time Frame: 4 years ]
  3. Relapse-free survival [ Time Frame: 4 years ]
  4. Event-free survival [ Time Frame: 4 years ]
  5. Overall survival [ Time Frame: 4 years ]
  6. Incidence and intensity of adverse events [ Time Frame: 8 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with confirmed diagnosis of acute myeloid leukemia (AML) or related precursor neoplasm, or acute leukemia of ambiguous lineage according to the current World Health Organization (WHO) classification, or patients with myelodysplastic syndrome (MDS) classified as refractory anemia with excess blasts-2 (RAEB-2)
  • Consent for a genetic assessment in AMLSG central laboratory
  • Patients considered eligible for intensive chemotherapy
  • ECOG performance status of ≤ 2
  • Age >= 18; there is no upper age limit
  • No prior chemotherapy for acute leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase; patients may have received prior therapy for myelodysplastic syndrome.
  • Non-pregnant and non-nursing. Due to the teratogenic potential of volasertib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) for 6 months after therapy is stopped. "Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months.
  • Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while receiving therapy and for 6 months after therapy is stopped, even if they have undergone a successful vasectomy
  • Signed written informed consent

Exclusion Criteria:

  • Patients with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); PML-RARA, or with variant translocations
  • Prior treatment with volasertib or any other PLK1 inhibitor
  • Performance status WHO >2 (see Appendix I)
  • Patients with ejection fraction <50% by echocardiography within 14 days of day 1
  • QTcF prolongation >470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome). The QTcF will be calculated as the mean of 3 ECGs taken at screening.
  • Any clinically significant, advanced or unstable disease or history of that may interfere with primary or secondary variable evaluations or put the patient at special risk, such as:

    • creatinine >1.5x upper normal serum level;
    • total bilirubin, AST or AP >2.5x upper normal serum level;
    • heart failure NYHA III/IV,
    • uncontrolled hypertension,
    • unstable angina,
    • serious cardiac arrhythmia;
    • severe obstructive or restrictive ventilation disorder
    • uncontrolled infection
  • Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
  • Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
  • Known or suspected active alcohol or drug abuse
  • Known positive for HIV, active HBV, HCV, or hepatitis A infection
  • Hematologic disorder independent of leukemia
  • No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.
  • No consent for biobanking.
  • Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study
  • Breast feeding women or women with a positive pregnancy test at Screening visit

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02198482


Locations
Germany
Hospital Aschaffenburg
Aschaffenburg, Germany, 63739
Helios Hospital Bad Saarow
Bad Saarow, Germany, 15526
Vivantes Hospital Am Urban
Berlin, Germany, 10967
Vivantes Hospital Neukölln
Berlin, Germany, 12351
Charite Berlin Campus Virchow Hospital
Berlin, Germany, 13353
Knappschaftskrankenhaus Bochum-Langendeer
Bochum, Germany, 44892
University Hospital Bonn
Bonn, Germany, 53105
Community Hospital Braunschweig
Braunschweig, Germany, 38114
Hospital Darmstadt
Darmstadt, Germany, 64283
University Hospital Düsseldorf
Düsseldorf, Germany, 40225
Hospital Essen, Protestant Hospital Essen-Werden
Essen, Germany, 45239
Hospital Esslingen
Esslingen, Germany, 73730
Malteser Hospital St. Franziskus
Flensburg, Germany, 24939
Hospital Frankfurt-Höchst
Frankfurt, Germany, 65929
Medical Care Unit Osthessen
Fulda, Germany, 36043
University Hospital Gießen
Gießen, Germany, 35392
Wilhelm-Anton-Hospital Goch
Goch, Germany, 47574
University Hospital Göttingen
Göttingen, Germany, 37075
University Hospital Hamburg-Eppendorf
Hamburg, Germany, 20246
Asklepios Hospital Altona
Hamburg, Germany, 22763
Hospital Hanau
Hanau, Germany, 63450
KRH Hospital Siloah-Oststadt-Heidehaus
Hannover, Germany, 30459
Hannover Medical School
Hannover, Germany, 30625
SLK-Hospital Heilbronn
Heilbronn, Germany, 74078
Marienhospital Herne
Herne, Germany, 44625
University Hospital des Saarlandes
Homburg/Saar, Germany, 66421
Community Hospital Karlsruhe
Karlsruhe, Germany, 76133
University Hospital Schleswig-Holstein
Kiel, Germany, 24105
Caritas Hospital Lebach
Lebach, Germany, 66822
Hospital Lippe-Lemgo
Lemgo, Germany, 32657
University Hospital Magdeburg
Magdeburg, Germany, 39120
University Hospital Johannes Gutenberg Mainz
Mainz, Germany, 55131
Johannes Wesling Hospital Minden
Minden, Germany, 32429
Stauferklinikum Schwäbisch-Gmünd
Mutlangen, Germany, 73557
Hospital Schwabing
München, Germany, 80804
Hospital rechts der Isar München
München, Germany, 81675
Hospital Oldenburg
Oldenburg, Germany, 26133
Hospital Passau
Passau, Germany, 94032
Hospital Stuttgart
Stuttgart, Germany, 70174
Diakonie Hospital Stuttgart
Stuttgart, Germany, 70176
Hospital Traunstein
Traunstein, Germany, 83278
Mutterhaus der Borromäerinnen
Trier, Germany, 54290
Hospital Barmherzige Brüder Trier
Trier, Germany, 54292
University Hospital Tübingen
Tübingen, Germany, 72076
University Hospital Ulm
Ulm, Germany, 89081
Sponsors and Collaborators
University of Ulm
Investigators
Principal Investigator: Hartmut Döhner, Prof. Dr. AMLSG Clinical Trials Office
Study Chair: Peter Paschka, MD University Hospital Ulm

Responsible Party: Prof. Dr. Hartmut Doehner, Prof. Dr., University of Ulm
ClinicalTrials.gov Identifier: NCT02198482     History of Changes
Other Study ID Numbers: AMLSG 20-13
2014-000477-39 ( EudraCT Number )
First Posted: July 23, 2014    Key Record Dates
Last Update Posted: February 28, 2018
Last Verified: February 2018

Keywords provided by Prof. Dr. Hartmut Doehner, University of Ulm:
Acute Myeloid Leukemia (AML)
Volasertib
High-risk Myelodysplastic Syndrome (MDS)

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Mitoxantrone
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors