A Phase II Study Evaluating the Efficacy and Safety of Bemcentinib in Patients With Myelodysplastic Syndromes Failing Standard of Care Therapy
Overview
- Phase
- Phase 2
- Intervention
- Bemcentinib
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- GWT-TUD GmbH
- Enrollment
- 45
- Locations
- 8
- Primary Endpoint
- Assessment of efficacy of Bemcentinib for the treatment of AML and MDS patients failing or being refractory to hypomethylating agent treatment
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This is an open-label, single-arm multicenter, phase II study. The primary objective is to assess the efficacy of bemcentinib (BGB324) a highly selective inhibitor of the AXL receptor tyrosine kinase for the treatment of AML and MDS patients failing or being refractory to first line hypomethylating agent (HMA) treatment. Furthermore, safety, disease progression, treatment failure will be assessed. A total of 43 patients will be included in the trial.
Detailed Description
Novel treatment options in patients with MDS or AML are urgently needed; treatment has not changed significantly over the past decades and survival is still dismal, especially in elderly patients not capable for an allogeneic stem cell transplantation and failing first line treatment with hypomethylating agents. Axl, a member of the Tyro3, Axl, Mer (TAM) receptor family, mediates proliferation and survival of leukemic cells and is upregulated upon cytostatic treatment. In addition, leukemic cells induce expression of the Axl ligand growth arrest-specific gene 6 (Gas6) in bone marrow stroma cells, which further amplifies their growth and therapy resistance. selective inhibition of Axl signaling by the small molecule Axl inhibitor bemcentinib blocked leukemic proliferation in vitro and in mouse models. It was shown that a blockade of the Gas6/Axl signaling axis by R428 (bemcentinib) significantly impaired MDS growth in an ex-vivo stroma-dependent co-culture setting using patient-derived primary material. These effects were especially observed in the CD34+ MDS stem cell compartment. A persistence of this stem cell compartment is expected to underlie drug resistance and/or drive disease progression in MDS. Thus, Axl represents a potential novel target in higher risk MDS and AML.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed written informed consent
- •Male and female ≥ 18 years at the first screening
- •Must be able to adhere to the study visit schedule and other protocol requirements
- •Initial diagnosis of AML or MDS according to WHO 2016 classification
- •At least one cytopenia (ANC \< 1800/μL or platelet count \< 100,000/μL or hemoglobin \< 10 g/dL)
- •Failure to achieve complete or partial response or hematological improvement after at least six (azacitidine) or four (decitabine) 4-week treatment cycles administered during the past two years OR Relapse after initial complete or partial response or hematological improvement observed after at least six (azacitidine) or four (decitabine) 4-week treatment cycles administered during the past two years OR Intolerance to treatment with HMAs during the past two years
- •Not eligible for allogeneic stem cell transplantation
- •≥ 5% bone marrow blasts at central morphology
- •Off all other treatments for AML/MDS for at least four weeks; G-CSF and erythropoietin are - allowed before and during the study as clinically indicated
- •ECOG performance status of 0-2
Exclusion Criteria
- •Prior intensive chemotherapy for MDS or AML
- •Radiotherapy or chemotherapy within the 14 days prior to the first dose of Bemcentinib being administered (other than hydroxyurea)
- •History of the following cardiac conditions:
- •Congestive cardiac failure of \> Class II severity according to the NYHA (defined as symptomatic at less than ordinary levels of activity)
- •Ischemic cardiac event including myocardial infarction within 3 months prior to first dose
- •Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (i.e. sustained systolic BP \>140 mmHg or diastolic BP \>90 mmHg), or need to change medication within 6 weeks of provision of consent due to lack of disease control
- •History or presence of sustained bradycardia (≤ 60 BPM), left bundle branch block, cardiac pacemaker or ventricular arrhythmia. (Note: Patients with a supraventricular arrhythmia requiring medical treatment, but with a normal ventricular rate are eligible )
- •Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least Grade 3 (QTc \> 450 ms at baseline)
- •Abnormal left ventricular ejection fraction on echocardiography or Multi Gated Acquisition Scan (MUGA) (less than the lower limit of normal for a patient of that age at the treating institution or \< 45 %, whichever is lower)
- •Current treatment with any agent known to cause Torsades de Pointes which cannot be discontinued at least five half-lives or two weeks prior to the first dose of study treatment. Please see Appendix XI for list of relevant medications
Arms & Interventions
Bemcentinib
Bemcentinib will be self-administered orally (fasted) at a dose mentioned above for a total of at least 4 cycles without a treatment-free period in between. Responding patients (as per criteria of European LeukaemiaNet and International MDS working Group (2006)) are eligible for up to 5 additional cycles according to the maintenance daily dosing of 2 x 1 capsules of 100 mg for each 28 days cycle (up to 9 cycles in total).
Intervention: Bemcentinib
Outcomes
Primary Outcomes
Assessment of efficacy of Bemcentinib for the treatment of AML and MDS patients failing or being refractory to hypomethylating agent treatment
Time Frame: 17 weeks
Overall hematological response rate
Secondary Outcomes
- Disease progression(up to 9 month)
- Treatment failure(up to 9 month)
- Toxicity measured by NCI CTCAE 5.0(up to 9 month)