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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03217838
Recruitment Status : Terminated (strategic decision)
First Posted : July 14, 2017
Last Update Posted : July 23, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE July 13, 2017
First Posted Date  ICMJE July 14, 2017
Last Update Posted Date July 23, 2021
Actual Study Start Date  ICMJE November 27, 2017
Actual Primary Completion Date March 25, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 4, 2019)
  • 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 of 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). Total complete remission includes patients with complete remission (CR), and complete remission with incomplete recovery (CRi). [ Time Frame: Up to 6 months ]
    Total complete remission includes patients with complete remission (CR), and complete remission with incomplete recovery (CRi).
Original Primary Outcome Measures  ICMJE
 (submitted: July 13, 2017)
  • 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).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2021)
  • 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 10⁹/L; independent 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 × 10⁹/L) or thrombocytopenia (< 100 × 10⁹/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 concentration of AZD2811 after single dose (Cmax) [ Time Frame: Days 1 and 4 of Cycle 1 (each cycle is 28 days) ]
  • Time to reach maximum AZD2811 plasma concentration (tmax) after single dose. [ Time Frame: Days 1 and 4 of Cycle 1 (each cycle is 28 days) ]
  • Area under the AZD2811 plasma concentration-time curve (AUC) [ Time Frame: Days 1 and 4 of Cycle 1 (each cycle is 28 days) ]
  • 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 (each cycle is 28 days) ]
  • Terminal elimination half-life (t1/2λz) of AZD2811 [ Time Frame: Days 1 and 4 of Cycle 1 (each cycle is 28 days) ]
  • Clearance (CL) of AZD2811 [ Time Frame: Days 1 and 4 of Cycle 1 (each cycle is 28 days) ]
  • Volume of distribution (Vz) for AZD2811 [ Time Frame: Days 1 and 4 of Cycle 1 (each cycle is 28 days) ]
  • Determine biological effective dose (BED) of AZD2811 in AML 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.
  • Maximum plasma concentration of venetoclax after single dose (Cmax) [ Time Frame: Cycle 1 Day 4 (each cycle is 28 days) ]
  • Time to reach maximum venetoclax plasma concentration (tmax) after single dose. [ Time Frame: Cycle 1 Day 4 (each cycle is 28 days) ]
  • Area under the venetoclax plasma concentration-time curve from zero to the time of the last measurable concentration [AUC(0-t)]. [ Time Frame: Cycle 1 Day 4 (each cycle is 28 days) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 13, 2017)
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticles as Monotherapy or in Combination in Acute Myeloid Leukemia Patients.
Official Title  ICMJE 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.
Brief Summary 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.
Detailed 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. 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

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.

Part A Group 1, Arm A - Day 1 and 4 Monotherapy Dose Escalation:

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. Approximately 22 patients will be enrolled.

Part A Group 1, Arm B - 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 addition to the Day 1 and 4 Q4W schedule. 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). Approximately 18 patients will be enrolled.

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.

A rolling 6 design will be applied to both of the AZD2811 and combination arms. The rolling 6 method 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.

Part A Group 2 Arm A - Day 1 and 4 Azacitidine Combination Escalation:

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 of body surface area subcutaneously (SC) in all territories or optionally/alternatively by IV in the United States (US) as per national prescribing information.

Part A Group 2 Arm B - Day 1, 4, 15, and 18 Azacitidine Combination Dose Escalation

In order to increase dose intensity during the 4 week cycle, and improve efficacy in the combination setting, AZD2811 will also be explored on the Days 1, 4, 15 and 18 schedule in the azacitidine combination and start at a lower daily dosage that has been shown to be safe while administered every 28 days. The proposed starting dose for this schedule is 300 mg/infusion AZD2811 on Day 1, 4, 15 and 18 (i.e., cumulative dose per 28 days is 1200 mg/Q4W) and standard dose and use of azacitidine 75 mg/m² of body surface area subcutaneously (SC) in all territories or optionally/alternatively by IV in the United States (US) as per national prescribing information. Approximately 18 patients will be enrolled.

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 A Group 3 Arm A - Day 1 and 4 Venetoclax Combination Dose Escalation

In Group 3 Arm A, AZD2811 is planned to be administered at 200 mg IV on Day 1 and Day 4 every 28 days (Q4W) and venetoclax is planned to be given (with a meal and water) at a dose of 100 mg orally (PO) on Day 1 and ramping up to 200 mg (PO) 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.

Further dose escalations of AZD2811 in Group 3 Arm A will occur at the discretion of the Safety Review Committee (SRC).

Part A Group 3 Arm B - Day 1, 4, 15, and 18 Venetoclax Combination Dose Escalation

If data from Groups 1 and/or 2 suggest that patients could benefit from a more intense AZD2811 dosing regimen, a schedule of venetoclax with AZD2811 dosing on Days 1, 4, 15 and 18 (see below) may be explored.

Group 3 Arm B will not exceed the registered venetoclax dose when combined with a starting dose of AZD2811 that is considered safe based on Group 3 Arm A observations. Subsequent cohorts will explore how to escalate AZD2811 in a more intensified schedule towards a recommended Phase 2 dose.

Part B - Dose Expansion

In Part B approximately 18 AML patients (6 additional patients in each group [AZD2811 monotherapy, Group 1], [AZD2811 in the azacitidine combination setting, Group 2], and [AZD2811 and venetoclax combination, Group 3]) will follow the affiliated dose/schedule from Part A that was found to be the most tolerable and/or efficacious.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukaemia
Intervention  ICMJE
  • Drug: AZD2811
    AZD2811 will be administered by IV infusion over 2 hours for doses <= 600 mg and by IV infusion over 4 hours for doses > 600 mg. AZD2811 will be given in 28-day cycles.
    Other Names:
    • AZD1152 hQPA
    • AZD1152 hydroxyl-quinazoline pyrazole anilide
  • Drug: Azacitidine

    Azacitidine is supplied in vials of 25 mg/mL powder for suspension for injection. After reconstitution, each vial contains a maximum of 100 mg.

    Patients should be pre-medicated for nausea and vomiting according to institutional standards before receiving azacitidine. Patients will receive 75 mg/m² on Days 1 through 7 or for 5 consecutive weekdays with rest on the 2 weekend days, and azacitidine dosing the first 2 weekdays of the next week of each 28-day cycle.

    Other Name: Vidaza (TM)
  • Drug: Venetoclax
    Venetoclax (VENCLEXTA®) is approved by the FDA for use in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Venetoclax is planned to be given at a dose of 100 mg orally (PO) on Day 1 and 200 mg (PO) 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.
    Other Name: Venclexta (TM)
Study Arms  ICMJE
  • Experimental: Part A - Group 1 Arm A: Monotherapy Dose Escalation
    AZD2811 single agent on Days 1 and 4 of each 28 day cycle. Dose escalation
    Intervention: Drug: AZD2811
  • Experimental: Part A - Group 1 Arm B: Monotherapy Dose Escalation
    AZD2811 single agent on Days 1, 4, 15, and 18 of each 28 day cycle. Dose Escalation
    Intervention: Drug: AZD2811
  • Experimental: Part A - Group 2 Arm A: AZD2811 plus Azacitidine Dose Escalation
    AZD2811 on Days 1 and 4 plus Azacitidine combination therapy. Escalating doses of AZD2811
    Interventions:
    • Drug: AZD2811
    • Drug: Azacitidine
  • Experimental: Part A - Group 3 Arm A: AZD2811 plus Venetoclax Dose Escalation
    AZD2811on Days 1 and 4 plus Venetoclax combination therapy. Escalating doses of AZD2811
    Interventions:
    • Drug: AZD2811
    • Drug: Venetoclax
  • Experimental: Part B - Group 1: AZD2811 Monotherapy Dose Expansion
    Monotherapy dose expansion. Additional patients will be enrolled at the AZD2811 MTD in the dose/schedule that was found most tolerable and/or efficacious.
    Intervention: Drug: AZD2811
  • Experimental: Part B - Group 2: AZD2811 plus Combination Drug Dose Expansion
    Combination therapy (either azacitidine or venetoclax) dose expansion. Additional patients will be enrolled at the AZD2811 combination MTD based on the dose/schedule from Part A that was found to be most tolerable and/or efficacious.
    Interventions:
    • Drug: AZD2811
    • Drug: Azacitidine
    • Drug: Venetoclax
  • Experimental: Part A - Group 2 Arm B: AZD2811 plus Azacitidine Dose Escalation
    AZD2811 on Days 1, 4, 15, and 18 plus azacitidine combination therapy. Escalating doses of AZD2811
    Interventions:
    • Drug: AZD2811
    • Drug: Azacitidine
  • Experimental: Part A - Group 3 Arm B: AZD2811 plus Venetoclax Dose Escalation
    AZD2811 on Days 1, 4, 15, and 18 plus Venetoclax combination therapy. Escalating doses of AZD2811
    Interventions:
    • Drug: AZD2811
    • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 22, 2021)
50
Original Estimated Enrollment  ICMJE
 (submitted: July 13, 2017)
36
Actual Study Completion Date  ICMJE March 25, 2021
Actual Primary Completion Date March 25, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  1. AML patients who have either: (a) relapsed or are refractory to standard therapies (the patient may have been treated with standard therapy prior to the diagnosis of AML e.g. for MDS), OR (b) diagnosis of AML (bone marrow blasts ≥ 20%), who are previously untreated for AML, and are not suitable for intensive induction therapy, as defined below (for AZD2811 monotherapy and HMA combination patients only i.e. inclusion criteria 1(b) may only be used to enrol a patient into Groups 1 and 2; previously untreated AML patients may not enrol into Group 3 UNLESS they fulfil inclusion criteria 1(a) above).

    Patients are unsuitable for intensive induction therapy if they are:

    • 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

    any significant co-morbidities which in the opinion of the treating physician makes the patient unsuitable for intensive induction therapy. This must be documented by the study monitor.

  2. AML patients who are unlikely to demonstrate rapid progression such that they would be unable to complete the first cycle of therapy.
  3. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses.
  4. Aged at least 18 years
  5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
  6. Prior treatment with hydroxyurea (up to 24 hours before study treatment) is allowed
  7. 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 (unconjugated hyperbilirubinemia) 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 x 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.

    Patients enrolled in the venetoclax combination part with a CLcr <80 mL/min (and ≥ 45 mL/min) as calculated by Cockcroft-Gault should be able to have more intensive prophylaxis and monitoring (according to institutional standard) to reduce the risk of TLS when initiating treatment with venetoclax.

  8. 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: a) Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, b) have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

9 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.

Exclusion criteria

  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 (except hydroxyurea), 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 monotherapy or with combination agent(s) 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 CYP3A 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: 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); current unstable or uncompensated respiratory or cardiac conditions; or uncontrolled hypertension; history of, or active, bleeding diatheses (e.g., haemophilia or von Willebrand disease); patients with inflammatory bowel disease (e.g., Crohn 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 IV anti-infective treatment within 2 weeks before first dose of study treatment unless either clear evidence would indicate that despite the clinical symptoms no infection took place, or just a single dose of IV antibiotics was administered followed by oral treatment thereafter.
  5. Any of the following cardiac criteria: a) Congestive heart failure (CHF) per New York Heart Association (NYHA) classification > Class II, b) Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, c) Unstable angina or new-onset angina, d) 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 (HMA 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:

    1. 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.
    2. 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. Adults with previously untreated diagnosis of AML (bone marrow blasts ≥ 20%), UNLESS they fulfil inclusion criterion 1(a) above.
  2. WBC count > 25,000 cells/mm3 (25 x 109/L); use of leukapheresis or hydroxyurea before venetoclax initiation is allowed to achieve this entry criterion (leukapheresis or hydroxyurea must be stopped at least 48 hours before the initiation of venetoclax).
  3. AML with known active central nervous system involvement.
  4. Chronic respiratory disease that requires continuous oxygen use.
  5. Previous venetoclax exposure that ended due to venetoclax toxicity.
  6. Use of moderate CYP3A inhibitor/inducers and P-gP inhibitors, with the exception of fluconazole and isavuconazole, that cannot be discontinued prior to Day 1 of dosing. Washout periods should be a minimum of 5 half-lives depending on the medication unless agreed upon with the Sponsor.
  7. Patient consumed grapefruit, grapefruit products, Seville oranges (including marmalades containing Seville oranges) or star fruit within 3 days before the initiation of venetoclax.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03217838
Other Study ID Numbers  ICMJE D6130C00003
HEMREF 41 ( Other Identifier: Sarah Cannon Development Innovations, LLC )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Howard Burris, MD SCRI Development Innovations, LLC
PRS Account AstraZeneca
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP