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Safety, Tolerability, and Efficacy of AZD2811 Nanoparticles in Patients With Relapsed AML/High-Risk Myelodysplastic Syndrome or Treatment-Naïve Patients.

This study is currently recruiting participants.
Verified November 2017 by AstraZeneca
Sponsor:
ClinicalTrials.gov Identifier:
NCT03217838
First Posted: July 14, 2017
Last Update Posted: November 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
AstraZeneca
  Purpose
This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 in patients with relapsed AML/high risk myelodysplastic syndrome or treatment-naïve patients not eligible for intensive induction therapy or allogeneic transplantation. The study was also explore the potential clinical activity by assessing anti-tumour activity in patients. The study will be conducted in two parts, designated Part A, dose escalation, and Part B, dose expansion.

Condition Intervention Phase
Acute Myeloid Leukaemia High-Risk Myelodysplastic Syndrome Drug: AZD2811 Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticle in Patients With Relapsed Acute Myeloid Leukaemia/High-Risk Myelodysplastic Syndrome or Treatment-Naïve Patients Not Eligible for Intensive Induction Therapy.

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Incidence of dose limiting toxicities (DLT) [ Time Frame: From the first day of study treatment up to the last day of Cycle 1 (28 days) ]
    The maximum tolerated dose (MTD) will be determined from the incidence of dose limiting toxicities (DLTs), adverse events (AEs), and abnormal laboratory test results.

  • Incidence od adverse events (AEs) [ Time Frame: From the first day of study treatment up to the last day of Cycle 1 (28 days) ]
    The maximum tolerated dose (MTD) will be determined from the incidence of dose limiting toxicities (DLTs), adverse events (AEs), and abnormal laboratory test results.

  • Incidence of abnormal laboratory test results [ Time Frame: From the first day of study treatment up to the last day of Cycle 1 (28 days) ]
    The maximum tolerated dose (MTD) will be determined from the incidence of dose limiting toxicities (DLTs), adverse events (AEs), and abnormal laboratory test results.

  • Antitumour activity of AZD2811 in patients by assessing total complete remission (CR). [ Time Frame: Up to 6 months ]
    Total complete remission includes patients with complete remission (CR), and complete remission with incomplete recovery (CRi).


Secondary Outcome Measures:
  • Overall Response Rate (ORR) [ Time Frame: Up to 6 months ]
    Overall response rate is the sum of CR + CRi + PR.

  • Complete Remission (CR) [ Time Frame: Up to 6 months. ]
    Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0 x 10^9/L; independence of red cell transfusions as described in Dohner H, et al. Blood. 2010;115:453-474

  • Complete Remission with incomplete recovery (CRi) [ Time Frame: Up to 6 months. ]
    All CR criteria except for residual neutropenia (< 1.0 × 10^9/L) or thrombocytopenia (< 100 × 10^9/L)

  • Partial Remission (PR) [ Time Frame: Up to 6 months. ]
    All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.

  • Overall Survival (OS) [ Time Frame: Up to 6 months ]
  • Maximum plasma drug concentration after single dose (Cmax) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  • Time to reach maximum plasma drug concentration (tmax) after single dose. [ Time Frame: Days 1 and 4 of Cycle 1 ]
  • Area under the plasma concentration-time curve (AUC) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  • Terminal elimination half-life (t1/2λz) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  • Clearance (CL) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  • Volume of distribution (Vz) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  • Determine biological effective dose (BED) of AZD2811 in AML/high-risk MDS patients in Part A. [ Time Frame: Up to 6 months ]
    BED is related to a clinical sign of activity of AZD2811, e.g., a blast cell reduction of > 50% at any time after AZD2811 administration.


Estimated Enrollment: 36
Actual Study Start Date: July 31, 2017
Estimated Study Completion Date: December 5, 2019
Estimated Primary Completion Date: December 5, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A
AZD2811 single agent dose escalation cohorts
Drug: AZD2811
AZD2811 is a potent and selective inhibitor of Aurora B kinase. It has been incorporated into a nanoparticle suitable for intravenous administration.
Experimental: Part B
Following the single agent dose escalation (Part A), additional evaluable patients will be enrolled at the maximum tolerated dose and/or below, in order to further explore the tolerability, PK and clinical activity at this dose (Part B).
Drug: AZD2811
AZD2811 is a potent and selective inhibitor of Aurora B kinase. It has been incorporated into a nanoparticle suitable for intravenous administration.

Detailed Description:

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 in patients with relapsed AML/high risk myelodysplastic syndrome or treatment-naïve patients not eligible for intensive induction therapy or allogeneic transplantation. The study was also explore the potential clinical activity by assessing anti-tumour activity in patients. The study will be conducted in two parts, designated Part A, dose escalation, and Part B, dose expansion.

In Part A the dose escalation and de-escalation plan for evaluating AZD2811 will follow the Bayesian Adaptive Design scheme which combines prior expectations about the dose toxicity relationship and applies the data at the end of each cohort to recommend a dose for the next cohort. Patients will receive a single 2- or 4- hour IV infusion on Day 1 and Day 4 of each 28-day cycle. Dosing frequency and schedule may be adjusted during the study on the basis of emerging safety and pharmacokinetic data.

Part B will include up to 24 additional evaluable patients at the maximum tolerated dose and/or below, in order to further explore the tolerability, PK and clinical activity at this dose.

  Eligibility

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, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Confirmed diagnosis of first relapsed AML (bone marrow or peripheral blood counts ≥ 5%) who have relapsed between 3 and 12 months following a full course of induction and consolidation chemotherapy (and are not candidates for allogeneic stem cell transplantation).
  2. AML patients > 70 years in first relapse or are refractory following at least 4 cycles of hypomethylating agents (azacytidine or decitabine).
  3. First relapsed/refractory high-risk MDS patients based on International Prognostic Scoring System (IPSS) of >4.5 - 6 (high) or >6 (very high).
  4. Previously untreated confirmed diagnosis of AML (bone marrow or peripheral blood counts ≥ 20%) or high risk MDS not suitable for intensive induction therapy or allogeneic transplantation based on the following: ≥ 70 years, or <70 with clinically significant cardiac or pulmonary dysfunction unrelated to leukemia.
  5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
  6. Adequate organ system function as defined by: PT/PTT/INR ≤ ULN; total bilirubin ≤ 1.5 mg/dL; ALT and AST < 2.5 x ULN if no liver involvement or ≤ 5 x ULN with liver involvement; creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance ≥ 50 mL/min as calculated by the Cockcroft-Gault method, or 24-hour measured urine creatinine clearance ≥ 50 mL/min.
  7. Females must be using adequate contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing.
  8. Sexually active male patients must use barrier contraception (i.e., condoms).

Exclusion Criteria:

  1. Second or later relapse.
  2. Treatment with any of the following: i) any investigational agent or study drugs from a previous clinical study within 4 half-lives; ii) any other chemotherapy, immunotherapy, or anticancer agents within 2 weeks; iii) any haematopoietic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF] within 7 days or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days of the first dose of study treatment; iv) Prescription or Non-Prescription drugs or other products known to be strong inhibitors/inducers of CYP3A4 that cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of the study medication; v) Allogeneic or autologous transplants; v) Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment).
  3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment.
  4. Presence of, or history of leptomeningeal disease.
  5. Evidence of severe or uncontrolled systemic diseases; history of, or active, bleeding diatheses; uncontrolled active systemic fungal, bacterial, viral, or other infection; or IV anti-infective treatment within 2 weeks.
  6. Any of the following cardiac criteria: i) Congestive heart failure (CHF) per NYHA classification > Class II; ii) Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy; iii) Unstable angina or new-onset angina; iv) QTcF interval > 470 ms on screening ECG.
  7. Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis).
  8. Chronic diarrhoea NCI CTCAE v4.03 Grade ≥ 2.
  9. History of infection with HIV.
  10. Serologic status reflecting active hepatitis B or C infection.
  11. Other comorbidity that the Investigator judges incompatible with intensive remission induction chemotherapy, which must be documented by the study monitor.
  Contacts and Locations
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): NCT03217838


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AstraZeneca Cancer Study Locator Service 1-877-400-4656 AstraZeneca@emergingmed.com

Locations
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Will Donnellan, MD SCRI Development Innovations, LLC
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03217838     History of Changes
Other Study ID Numbers: D6130C00003
HEMREF 41 ( Other Identifier: Sarah Cannon Development Innovations )
First Submitted: July 13, 2017
First Posted: July 14, 2017
Last Update Posted: November 9, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
AML
Acute Myeloid Leukaemia
High-Risk Myelodysplastic Syndrome
AZD2811
AZD1152
AZD1152 hQPA
barasertib

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