Clinical Trials /

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), and schedule, safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) patients or treatment-naïve AML patients not eligible for intensive induction therapy. In addition, the study will explore the potential clinical activity by assessing anti-tumour activity in patients. There are two parts to this study: Part A, dose escalation, and Part B, dose expansion.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not 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 Acute Myeloid Leukemia Patients.
  • Official Title: A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 as Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia 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

Interventions

DrugSynonymsArms
AZD2811AZD1152 hQPA, AZD1152 hydroxyl-quinazoline pyrazole anilidePart A - AZD2811 plus Azacitidine Dose Escalation
AzacitidineVidaza (TM)Part A - AZD2811 plus Azacitidine Dose Escalation
VenetoclaxVenclexta (TM)Part A - AZD2811 plus Venetoclax Dose Escalation

Purpose

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) patients or treatment-naïve AML 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 monotherapy or with
      combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) patients or
      treatment-naïve AML 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. Patients will be enrolled in either Part A or Part B according to the
      Investigator's judgment of the most appropriate treatment for the individual patient and slot
      availability.

      Part A - Dose Escalation

      Arm 1 - Day 1 and 4 monotherapy dose escalation:

      Approximately 48 evaluable treatment-naïve AML patients not eligible for intensive induction
      therapy or relapsed/refractory AML patients will be enrolled in Arm 1 and Arm 2 of 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 and schedule for the next
      cohort. The total number of patients will depend upon the number of dose escalations,
      de-escalations, and schedule changes 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.

      Arm 2 - Day 1, 4, 15, and 18 monotherapy dose escalation:

      A Day 1, 4, 15, and 18 every 4 weeks or 28 days (Q4W) schedule will be investigated in Arm 2.
      The proposed starting dose for this schedule is 300 mg/infusion AZD2811 on Day 1, 4, 15 and
      18 (i.e. cumulative dose 1200 mg/Q4W). This starting dose is less than daily doses shown to
      be tolerated in the AML setting, and the cumulative cycle dose/Q4W does not exceed the
      highest dose shown to be tolerated (600 mg/infusion Day 1, 4 cumulative 1200 mg Q4W).

      Combination Escalation:

      AZD2811 can be escalated (in the combination setting) independent of the monotherapy dose
      explored, after thorough examination of the available safety data. The combination therapy
      exploration will not impact the dose to be further explored in the monotherapy setting nor
      will the monotherapy impact the dose in the combination setting. As such, the number of
      cohorts in the monotherapy setting can differ from the number of cohorts in the combination
      setting. The safety observations of the monotherapy will be considered by the Safety Review
      Committee (SRC) in the overall decision-making process for subsequent dose exploration
      decision.

      Azacitidine Combination:

      A starting dose of 400 mg of AZD2811 will be used for investigation in combination with the
      standard dose of the hypomethylating agent (HMA) azacitidine. In this dose escalation part,
      approximately 12-15 evaluable treatment-naïve AML patients not eligible for intensive
      induction therapy or relapsed/refractory AML will be enrolled and dosed in ascending doses of
      AZD2811 and standard dose of azacitidine at 75 mg/m² subcutaneously (SC) in all territories
      or optionally/alternatively by IV in the United States (US) as per national prescribing
      information.

      AZD2811 will be administered over 2 hours for doses up to and including 600 mg and over 4
      hours for doses exceeding 600 mg on Days 1 and 4 of each 28-day cycle. Patients will receive
      75 mg/m² of azacitidine on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5)
      with a treatment holiday on the two weekend days (Days 6 and 7), and azacitidine dosing on
      the first 2 weekdays of the next week (Days 8 and 9) of each 28-day cycle.

      A rolling 6 design will be applied to the AZD2811 + HMA combination group which allows
      accrual of 3 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.

      Venetoclax Combination:

      Approximately 18-21 evaluable relapsed/refractory AML patients will be enrolled and dosed
      with AZD2811 and venetoclax. In cohort 1v, AZD2811 will be administered at 200 mg IV on Days
      1 and 4 every 28 days (Q4W) and venetoclax will be given 100 mg orally (PO) on Day 1 and 200
      mg (PO) with a meal and water on Days 2- 28 for the 1st cycle. The third patient in cohort 1
      (AZD2811 at 200 mg) will only be enrolled after the first 2 patients have received ≥ 2 weeks
      of treatment and have shown no evidence of toxicity observed to be compatible with a DLT, and
      further dose escalations of AZD2811 will occur at the discretion of the Safety Review
      Committee (SRC)

      The dose of AZD2811 can be escalated (in the combination setting) independent of the
      monotherapy dose explored, after thorough examination of the available safety data of the
      current and the previous cohorts. The combination therapy exploration will not impact the
      dose further explored in the monotherapy setting nor will the monotherapy impact the dose in
      the combination setting. As such, the number of cohorts in the monotherapy setting can differ
      from the number of cohorts in the combination setting. The safety observations of the
      monotherapy will be considered by the Safety Review Committee (SRC) in the overall
      decision-making process for subsequent dose exploration decision.

      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 the
      combination setting (Group 2, 40 patients) in order to further explore the tolerability, PK
      and clinical activity at this dose.
    

Trial Arms

NameTypeDescriptionInterventions
Part A - Arm 1 Dose EscalationExperimentalAZD2811 single agent on Days 1 and 4 of each 28 day cycle. Dose escalation
  • AZD2811
Part A - Arm 2 Dose EscalationExperimentalAZD2811 single agent on Days 1, 4, 15, and 18 of each 28 day cycle. Dose Escalation
  • AZD2811
Part A - AZD2811 plus Azacitidine Dose EscalationExperimentalAZD2811 plus azacitidine combination therapy. Escalating doses of AZD2811
  • AZD2811
  • Azacitidine
Part A - AZD2811 plus Venetoclax Dose EscalationExperimentalAZD2811 plus venetoclax combination therapy. Escalating doses of AZD2811
  • AZD2811
  • Venetoclax
Part B - Group 1 AZD2811 Monotherapy Dose ExpansionExperimentalMonotherapy dose expansion. Additional patients will be enrolled at the AZD2811 MTD.
  • AZD2811
Part B - Group 2 AZD2811 plus Combination Drug Dose ExpansionExperimentalCombination therapy (either azacitidine or venetoclax) dose expansion. Additional patients will be enrolled at the AZD2811 combination MTD.
  • AZD2811
  • Azacitidine
  • Venetoclax

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) is 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 serum 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. Adults with previously untreated confirmed diagnosis of AML (bone marrow blasts ≥ 20%)
             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
                  protocol.

               -  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 AZD2811 with or without azacitidine
                  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 should be a minimum of 5 half-lives depending on the
                  medication.

               -  Patients who have undergone allogeneic stem cell transplant within 12 months are
                  excluded. If allogeneic transplant was > 12 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]); or other malignancy (like advanced malignant
             hepatic tumours); 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 unless clear evidence would indicate that despite the clinical
             symptoms no infection took place.

          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.

        Additional exclusion criteria - venetoclax combination:

          1. WBC count ≤ 25,000 cells/mm³ (25 x 10 exp 9/L); use of leukapheresis or hydroxyurea
             (48 hours) before venetoclax initiation is allowed to achieve this entry criterion.

          2. AML with known active central nervous system involvement.

          3. Chronic respiratory disease that requires continuous oxygen use.

          4. Previous venetoclax exposure that ended due to venetoclax toxicity.

          5. In addition to strong CYP3A inhibitor/inducers, moderate CYP3A inhibitor/inducers and
             P-gP inhibitors cannot be discontinued prior to Day 1 of dosing and withheld
             throughout the first 4 weeks of study start. Washout periods should be a minimum of 5
             half-lives depending on the medication.

          6. Patient consumed grapefruit, grapefruit products, Seville oranges (including
             marmalades containing Seville oranges) or star fruit within 3 days before the
             initiation of venetoclax.
      
Maximum Eligible Age:130 Years
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 10⁹/L; independent 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 × 10⁹/L) or thrombocytopenia (< 100 × 10⁹/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 concentration of AZD2811 after single dose (Cmax)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Time to reach maximum AZD2811 plasma concentration (tmax) after single dose.
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Area under the AZD2811 plasma concentration-time curve (AUC)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Area under the AZD2811 plasma concentration-time curve from zero to the time of the last measurable concentration [AUC(0-t)].
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Terminal elimination half-life (t1/2λz) of AZD2811
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Clearance (CL) of AZD2811
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Volume of distribution (Vz) for AZD2811
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Determine biological effective dose (BED) of AZD2811 in AML 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.
Measure:Maximum plasma concentration of venetoclax after single dose (Cmax)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Time to reach maximum venetoclax plasma concentration (tmax) after single dose.
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Area under the venetoclax plasma concentration-time curve (AUC)
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Area under the venetoclax plasma concentration-time curve from zero to the time of the last measurable concentration [AUC(0-t)].
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Terminal elimination half-life (t1/2λz) of venetoclax
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Clearance (CL) of venetoclax
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:
Measure:Volume of distribution (Vz) for venetoclax
Time Frame:Days 1 and 4 of Cycle 1
Safety Issue:
Description:

Details

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

Trial Keywords

  • AML
  • Acute Myeloid Leukaemia
  • AZD2811
  • AZD1152
  • AZD1152 hQPA
  • barasertib
  • azacitidine
  • VIDAZA®
  • venetoclax
  • VENCLEXTA®

Last Updated

March 11, 2020