Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes

Myelodysplastic Syndromes Clinical Trial

Official title:

An Open Label, Phase I Trial of Intravenous Administration of Volasertib as Monotherapy and in Combination With Azacitidine in Patients With Myelodysplastic Syndrome After Hypomethylating Agents Treatment Failure

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02721875
• Other study ID #: 1230.43
• Secondary ID: 2015-004490-32
• Status: Terminated
• Phase: Phase 1
• Start date: April 28, 2016
• Est. completion date: July 29, 2016

Study information

• Verified date: August 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objectives of this trial are to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics and preliminary efficacy of volasertib in two dosing schedules of intravenous volasertib as monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome (MDS) after hypomethylating agents (HMA) treatment failure.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: July 29, 2016
• Est. primary completion date: June 29, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Patients 18 years and older with diagnosis of WHO classification-defined primary or treatment-related myeloid neoplasms classified as follows:

• Refractory anaemia with excess blasts (RAEB)-1 (5%-9% marrow blasts) or

• RAEB-2 (10%-19% marrow blasts or 5% - 19% peripheral blast) or

• Chronic Myelomonocytic Leukaemia (CMML) (5%-19% blasts) with white blood cell (WBC) count <13000/mm3 or

• Acute Myeloid Leukaemia (AML) (20%-29% marrow blasts, i.e., RAEB-t according to French-American-British [FAB] classification) with WBC count <10000/mm3

• Patients classified as intermediate, high or very high-risk according to Revised - International Prognostic Scoring System (IPSS-R) at the time of enrolment

• Patients who have received a maximum of 24 cycles of frontline HMA treatment prior to enrolment.

• Patients must have received a minimum prior dosing schedule of either:

• Azacitidine 75 mg/m2 x 5 days per cycle or 50 mg/m2 x 7 days per cycle, or

• Decitabine 20 mg/m2 x 5 days per cycle, or

• SGI-110 60 mg/m2 x 5 days per cycle

• Patients must meet either one of the following criteria:

• Progressive disease (PD, according to 2006 International Working Group (IWG) criteria) at any time after initiation of the prior HMA treatment, or

• Relapse after initial complete (CR) or partial remission (PR) or haematological improvement (HI) (according to 2006 IWG criteria); or

• Failure to achieve complete or partial remission or HI (according to 2006 IWG) with no evidence of progression (i.e., Stable Disease [SD]) after at least six cycles of prior azacitidine treatment or at least four cycles of other prior HMA treatment.

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 at screening

• Signed written informed consent consistent with International Conference of Harmonization Good Clinical Practice (ICH-GCP) and local legislation

Exclusion criteria:

• Prior systemic therapy (including investigational drugs) for MDS, CMML or AML within 14 days before treatment with study medication.

• Patients requiring intervention for white blood cell count control with hydroxyurea, chemotherapy, or leukapheresis.

• Prior exposure to more than one line of HMA based treatment.

• Prior exposure to volasertib or other polo-kinase inhibitors

• Patients who were unable to tolerate prior HMA treatment

• Patients with history of hematopoietic stem cell transplant (HSCT)

• Known hypersensitivity to the trial drugs or its excipients

• Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment, e.g., in prostate or breast cancer).

• QTcF value >470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Volasertib

• Volasertib

• Azacitidine

Locations

Country	Name	City	State
Japan	University of Fukui Hospital	Fukui, Yoshida-gun

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle	DLT was defined as any of the following adverse events (AEs) considered to be related to study drug: 1. Common terminology criteria for adverse events (CTCAE) v4.03 =Grade 3 drug related non- haematological toxicity, excluding; =Grade 3 untreated nausea, vomiting or diarrhea. Any laboratory abnormality - not considered clinically significant by investigator or resolved spontaneously or could have been recovered with appropriate treatment within 7 days. Grade 3 infection which could be recovered with appropriate treatment within 7 days. Azacitidine injection site reaction or complications related to azacitidine injection. 2. Febrile neutropenia as defined by CTCAE which could not recovered with appropriate treatment within 7 days. 3. Inability to deliver full dose of volasertib according to the assigned dose level within Cycle 1 due to drug-related AEs. 4. Haematological DLTs. 5. Any other drug-related AEs that resulted in the delay of starting new treatment cycle for =4 weeks.	First treatment cycle, up to 28 days
Primary	Maximum Tolerated Dose (MTD) of Volasertib	The MTD was defined as the highest dose with less than 35% risk of the true dose limiting toxicities (DLT) rate being above 0.33 for schedule A, and the highest dose with less than 40% risk of the true DLT rate being above 0.33 for schedule B. The phase I dose-finding was to be guided by a Bayesian 2-parameter logistic regression model (BLRM) with overdose control in each schedule separately.	First treatment cycle, up to 28 days
Secondary	Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria	Objective response defined as best overall response of complete remission, partial remission or haematological improvement according to the International Working Group 2006 criteria. It is based on Complete remission (CR): Bone marrow: <=5% myeloblasts with normal maturation of all cell lines, Peripheral blood: Hemoglobin >=11 Grams Per Decilitre (g/dL), Platelets >=100 x 109/L, Neutrophils >=1.0 x 109/L, Blasts 0%. Peripheral blood responses had to last at least 4 weeks to qualify for CR. Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by >=50% to baseline but still >5%, Cellularity and morphology not relevant. Peripheral blood responses must last at least 4 weeks to qualify for PR. Haematological improvement (HI): HI was evaluated in patients with abnormal pretreatment values based on Erythroid response, Platelet response, Neutrophil response. Peripheral blood responses had to last at least 8 weeks to qualify for HI.	Up to 168 days
Secondary	Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy)	Area under the plasma concentration-time curve over the time interval from zero to the last measured time point tz of volasertib (AUC0-tz) (for monotherapy).	Pharmacokinetic (PK) samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration
Secondary	Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy)	Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).	PK samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration
Secondary	Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity of Volasertib (AUC0-8) (for Combination)	Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-8) (for combination).	PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine
Secondary	Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination)	Maximum measured plasma concentration of volasertib (Cmax) (for combination).	PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine

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