Symptoms and General Pathology

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Neoplasms

Blood and Lymph Conditions

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Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

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Antineoplastic Agents

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Azacitidine

Antimetabolites

Enzyme Inhibitors

Volasertib

Boehringer Ingelheim

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.

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

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

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.

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.

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.

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).

Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination).

Maximum measured plasma concentration of volasertib (Cmax) (for combination).

Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle

Volasertib Monotherapy

Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle

Volasertib + Azacitidine Combination

Total

Age, Continuous

Sex: Female, Male

All patients who were documented to receive at least one dose of volasertib were defined as the treated set (TS).

Trial was prematurely discontinued and only one patient was treated. So it was not possible to draw any conclusion about volasertib monotherapy/with azacitidine, in patients with Myelodysplastic syndrome after Hypomethylating agent treatment failure

Boehringer Ingelheim, Call Center

Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle

Maximum Tolerated Dose (MTD) of Volasertib

Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria

Cycle 1 - Day 1

Cycle 1 - Day 8

All evaluable patients were to be included in the PK analysis. Patients who were considered as not evaluable were to be listed with their individual plasma concentrations and individual PK parameters; however, they were not to be included in descriptive statistics for plasma concentrations.

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)

All evaluable patients were to be included in the Pharmacokinetic (PK) analysis. Patients who were considered as not evaluable were to be listed with their individual plasma concentrations and individual PK parameters; however, they were not to be included in descriptive statistics for plasma concentrations.

Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy)

Due to premature discontinuation of the trial no patient is recruited for combination therapy.

Spots Global Cancer Trial Database for Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes

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