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Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticles as Monotherapy or in Combination in Acute Myeloid Leukemia Patients.

NCT03217838

Description:

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 with or without azacitidine in patients with relapsed AML or treatment-naïve patients not eligible for intensive induction therapy. The study will 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

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticles as Monotherapy or in Combination in Myeloid Leukemia/Myelodysplastic Syndrome Patients.
  • Official Title: A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticle as Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia/Myelodysplastic Syndrome Patients Not Eligible for Intensive Induction Therapy.

Clinical Trial IDs

  • ORG STUDY ID: D6130C00003
  • SECONDARY ID: HEMREF 41
  • NCT ID: NCT03217838

Conditions

  • Acute Myeloid Leukaemia
  • High-Risk Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
AZD2811AZD1152 hQPA, AZD1152 hydroxyl-quinazoline pyrazole anilidePart A Monotherapy
AzacitidineVidaza (TM)Part A Combination Therapy

Purpose

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 with or without azacitidine in patients with relapsed AML/myelodysplastic syndrome (MDS) or treatment-naïve patients not eligible for intensive induction therapy. The study will 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

Detailed Description

      This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety,
      tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 with or without azacytidine
      in patients with relapsed AML/myelodysplastic syndrome (MDS) or treatment-naïve AML/MDS
      patients not eligible for intensive induction therapy. The study will 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.

      Part A - Dose Escalation

      Monotherapy Escalation: Approximately 36 evaluable treatment-naïve AML/MDS patients not
      eligible for intensive induction therapy or relapsed/refractory AML/MDS patients will be
      enrolled in the monotherapy escalation in Part A of this study.

      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. The
      total number of patients will depend upon the number of dose escalations/de-escalations
      necessary. At least 3 and up to 6 evaluable patients will be required for each dose 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.

      Combination Escalation: The dose of AZD2811 chosen for investigation in combination with the
      standard dose of the hypomethylating agent (HMA) azacitidine will not exceed the dose that
      was found tolerable as monotherapy. In this dose escalation part, approximately 12-15
      evaluable treatment-naïve AML/MDS patients not eligible for intensive induction therapy or
      relapsed/refractory AML/MDS will be enrolled and dosed in ascending doses of AZD2811 and
      standard dose of azacitidine at 75 mg/m2 subcutaneously (SC) or by IV.

      The combination group will use a rolling 6 method which allows accrual of 2 to 6 patients
      concurrently onto a dose level based on the numbers of patients who are currently enrolled
      and evaluable, who experience a DLT, and who remain at risk of developing a DLT.

      Part B - Dose Expansion

      Part B will include up to 80 treatment-naïve AML patients not eligible for intensive
      induction therapy at the MTD in AZD2811 monotherapy (Group 1, 40 patients) and AZD2811 in
      combination with azacitidine (Group 2, 40 patients) in order to further explore the
      tolerability, PK and clinical activity at this dose.
    

Trial Arms

NameTypeDescriptionInterventions
Part A MonotherapyExperimentalAZD2811 single agent dose escalation cohorts
  • AZD2811
Part B MonotherapyExperimentalAdditional evaluable patients will be enrolled at up to the maximum tolerated dose of AZD2811 in order to further explore the tolerability, PK and clinical activity at this dose.
  • AZD2811
Part A Combination TherapyExperimentalCombination Escalation: The dose of AZD2811 chosen for investigation in combination with azacitidine will not exceed the dose that was found tolerable as monotherapy. Ascending doses of AZD2811 and azacitidine at 75 mg/m2 subcutaneously (SC) or by IV will be given. The combination group will use a rolling 6 method which allows accrual of 2 to 6 patients concurrently onto a dose level based on the numbers of patients who are currently enrolled and evaluable, who experience a DLT, and who remain at risk of developing a DLT.
  • AZD2811
  • Azacitidine
Part B Combination TherapyExperimentalAdditional evaluable patients will be enrolled at up to the maximum tolerated dose of AZD2811 in order to further explore the tolerability, PK and clinical activity at this dose.
  • AZD2811
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria for All Patients:

          1. Provision of signed and dated, written informed consent prior to any study-specific
             procedures, sampling or analyses.

          2. ≥ 18 years of age

          3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

          4. Prior treatment with hydroxyurea (up to 24 hours before study treatment) and
             corticosteroid or lenalidomide for MDS are allowed.

          5. Adequate organ system function as outlined below:

             PT/PTT ≤1.5 x upper limit of normal (ULN)

             Total bilirubin ≤1.5 x ULN. Patients with documented Gilbert's Syndrome who have serum
             bilirubin ≤3 x the ULN may be enrolled, unless there is evidence of hemolytic anemia

             Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ˂2.5 × ULN if no
             liver involvement or ≤5 times the 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

          6. Other comorbidity that the Investigator judges incompatible with intensive remission
             induction chemotherapy, which must be documented by the study monitor.

          7. Females should be using adequate contraception, should not be breast feeding and must
             have a negative pregnancy test prior to start of dosing if of child-bearing potential
             or must have evidence of non-child-bearing potential by fulfilling one of the
             following criteria at screening:

             Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12
             months following cessation of all exogenous hormonal treatments

             Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
             oophorectomy or bilateral salpingectomy but not tubal ligation

          8. Sexually active male patients should be willing to use barrier contraception i.e.,
             condoms. Female partners of male patients should also use a highly effective form of
             contraception if they are of childbearing potential, unless the male patient is
             abstaining from sexual intercourse.

        Part A (Dose Escalation) Inclusion Criteria:

          1. AML patients who have relapsed or are refractory to standard therapies.

          2. AML patients who are unlikely to demonstrate rapid progression such that they would be
             unable to complete the first cycle of therapy.

          3. Relapsed/refractory intermediate-1, intermediate-2. and high-risk MDS patients based
             on the Revised International Prognostic Scoring System (IPSS).

          4. MDS patients who are unlikely to demonstrate rapid progression such that they would be
             able to complete the first cycle of therapy.

          5. Adults with previously untreated confirmed diagnosis of AML (bone marrow blasts ≥ 20%)
             or MDS for whom monotherapy with AZD2811 is considered appropriate and are not
             suitable for intensive induction therapy based on the following:

               -  75 years or <75 years of age with clinically significant cardiac or pulmonary
                  dysfunction unrelated to leukaemia, as reflected by at least 1 of the following
                  criteria:

        Left ventricular ejection fraction (LVEF) ≤50%

        Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% of expected

        Forced expiratory volume 1 (FEV1) ≤65% of expected

        Chronic stable angina

        Part B (Dose Expansion) Inclusion Criterion

        1. Adults with previously untreated confirmed diagnosis of AML per World Health
        Organization (WHO) and European Leukemia Net (ELN) criteria (bone marrow blasts ≥ 20%) who
        are not suitable for intensive induction therapy based on the following:

        ≥75 years or <75 years of age with clinically significant cardiac or pulmonary dysfunction
        unrelated to leukaemia, as reflected by at least 1 of the following criteria:

        Left ventricular ejection fraction (LVEF) ≤50%

        Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% of expected

        Forced expiratory volume 1 (FEV1) ≤65% of expected

        Chronic stable angina

        Exclusion Criteria:

        Patients must not enter the study if any of the following exclusion criteria are fulfilled

          1. Treatment with any of the following:

             Any investigational agents, experimental antibody or antibody drug conjugates, or
             study drugs from a previous clinical study within 3-4 weeks of said prior
             investigational agent(s) with regard to the first dose of study treatment on this CSP

             Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the first
             dose of study treatment

             Any haematopoietic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])
             within 7 days of the first dose of investigational product or pegylated G-CSF
             (pegfilgrastim) or darbepoetin within 14 days of the first dose of study treatment.

             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 study drug. Washout
             periods vary between 1 to 5 weeks depending on the medication.

             Patients who have undergone allogeneic stem cell transplant within 6 months are
             excluded. If allogeneic transplant was > 6 months ago, then they are not excluded as
             long as they are off all immunosuppression and have no signs or symptoms of active
             graft versus host disease.

             Major surgery (excluding placement of vascular access) within 4 weeks of the first
             dose of study treatment.

          2. With the exception of alopecia, any unresolved toxicities from prior therapy greater
             than CTCAE Grade 1 at the time of starting study treatment.

          3. Presence of, or history of leptomeningeal disease.

          4. As judged by the Investigator, any evidence of: a) severe or uncontrolled systemic
             diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral,
             diffuse, parenchymal lung disease]); b) current unstable or uncompensated respiratory
             or cardiac conditions; c) uncontrolled hypertension; d) history of, or active,
             bleeding diatheses (e.g., haemophilia or von Willebrand disease); e) patients with
             inflammatory bowel disease (e.g., Crohn's or colitis ulcerosa); uncontrolled active
             systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing
             signs/symptoms related to the infection and without improvement, despite appropriate
             antibiotics or other treatment); or f) IV anti-infective treatment within 2 weeks
             before first dose of study treatment.

          5. Any of the following cardiac criteria:

             Congestive heart failure (CHF) per New York Heart Association (NYHA) classification >
             Class II

             Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

             Unstable angina or new-onset angina

             QTcF interval > 450 ms (for male subjects) or >470 ms (for female subjects) on
             screening ECG

          6. Active non-infectious skin disease (including rash, dermatitis, or psoriasis, but
             excluding stable plaque psoriasis from the definition of active disease). Patients
             with a rash that is biopsy-proven leukaemia or with pressure ulcers are not excluded.
             Patients with petechiae from thrombocytopenia or patients with drug related rashes
             that are improving are not excluded.

          7. Patients with a known hypersensitivity to azacitidine or mannitol (Combination
             patients only).

          8. History of hypersensitivity to active or inactive excipients (e.g., PEG) of any drug
             in the study or drugs with a similar chemical structure or class to those investigated
             in the study.

          9. Known history of infection with human immunodeficiency virus (HIV)

         10. Serologic status reflecting active hepatitis B or C infection:

        Subjects who are anti-HBc positive and who are surface antigen negative will need to have a
        negative PCR result before enrolment. Those who are hepatitis B surface antigen positive or
        hepatitis B polymerase chain reaction (PCR) positive will be excluded.

        Subjects who are hepatitis C antibody positive will need to have a negative PCR result
        before enrolment. Those who are hepatitis C PCR positive will be excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description:The maximum tolerated dose (MTD) will be determined from the incidence of dose limiting toxicities (DLTs), adverse events (AEs), and abnormal laboratory test results.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to 6 months
Safety Issue:
Description:Overall response rate is the sum of CR + CRi + PR.
Measure:Complete Remission (CR)
Time Frame:Up to 6 months.
Safety Issue:
Description: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
Measure:Complete Remission with incomplete recovery (CRi)
Time Frame:Up to 6 months.
Safety Issue:
Description:All CR criteria except for residual neutropenia (< 1.0 × 10^9/L) or thrombocytopenia (< 100 × 10^9/L)
Measure:Partial Remission (PR)
Time Frame:Up to 6 months.
Safety Issue:
Description: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%.
Measure:Overall Survival (OS)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Maximum plasma drug concentration after single dose (Cmax)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Time to reach maximum plasma drug concentration (tmax) after single dose.
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve (AUC)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Terminal elimination half-life (t1/2λz)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Clearance (CL)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Volume of distribution (Vz)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Determine biological effective dose (BED) of AZD2811 in AML/high-risk MDS patients in Part A.
Time Frame:Up to 6 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • AML
  • Acute Myeloid Leukaemia
  • High-Risk Myelodysplastic Syndrome
  • AZD2811
  • AZD1152
  • AZD1152 hQPA
  • barasertib
  • azacitidine
  • Vidaza

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