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

NCT02721875 | Terminated Phase 1 Results

• 2 other identifiers: 1230.432015-004490-32
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (5)

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

  Up to 168 days

• 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

• 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

• Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity of Volasertib (AUC0-∞) (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

• 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

Study Arms (2)

Volasertib monotherapy

EXPERIMENTAL

Drug: Volasertib

Volasertib + azacitidine combination

EXPERIMENTAL

Drug: Volasertib; Drug: Azacitidine

Interventions

Volasertib DRUG

Volasertib monotherapy

Azacitidine DRUG

Volasertib + azacitidine combination

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (1)

University of Fukui Hospital

Fukui, Yoshida-gun, 910-1193, Japan

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

BI 6727; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Limitations and Caveats

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

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

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 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2016
• First Posted: March 29, 2016
• Study Start: April 28, 2016
• Primary Completion: June 29, 2016
• Study Completion: July 29, 2016
• Last Updated: August 9, 2018
• Results First Posted: August 9, 2018

Record last verified: 2018-08

Locations

JP (1)