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

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ClinicalTrials.gov Identifier: NCT03217838
Recruitment Status : Recruiting
First Posted : July 14, 2017
Last Update Posted : June 21, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukaemia Drug: AZD2811 Drug: Azacitidine Phase 1 Phase 2

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 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.

Part A - Dose Escalation

Monotherapy Escalation: Approximately 36 evaluable treatment-naïve AML patients not eligible for intensive induction therapy or relapsed/refractory AML 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 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) or by IV. 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.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Non-Randomized
Intervention Model: Parallel 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 as Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia Patients Not Eligible for Intensive Induction Therapy.
Actual Study Start Date : July 31, 2017
Estimated Primary Completion Date : February 9, 2021
Estimated Study Completion Date : August 13, 2021


Arm Intervention/treatment
Experimental: Part A Monotherapy
AZD2811 single agent dose escalation cohorts
Drug: AZD2811

AZD2811 is a frozen sterile nanoparticle suspension for constitution for infusion. Each vial contains 10 mg/mL.

AZD2811 will be administered by IV infusion over 2 hours for doses up to and including 600 mg and by IV infusion over 4 hours for doses above 600 mg. AZD2811 will be given on Days 1 and 4 of each 28-day cycle.

Other Names:
  • AZD1152 hQPA
  • AZD1152 hydroxyl-quinazoline pyrazole anilide

Experimental: Part B Monotherapy
Additional 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.
Drug: AZD2811

AZD2811 is a frozen sterile nanoparticle suspension for constitution for infusion. Each vial contains 10 mg/mL.

AZD2811 will be administered by IV infusion over 2 hours for doses up to and including 600 mg and by IV infusion over 4 hours for doses above 600 mg. AZD2811 will be given on Days 1 and 4 of each 28-day cycle.

Other Names:
  • AZD1152 hQPA
  • AZD1152 hydroxyl-quinazoline pyrazole anilide

Experimental: Part A Combination Therapy

Combination 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.

Drug: AZD2811

AZD2811 is a frozen sterile nanoparticle suspension for constitution for infusion. Each vial contains 10 mg/mL.

AZD2811 will be administered by IV infusion over 2 hours for doses up to and including 600 mg and by IV infusion over 4 hours for doses above 600 mg. AZD2811 will be given on Days 1 and 4 of each 28-day cycle.

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)

Experimental: Part B Combination Therapy
Additional 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.
Drug: AZD2811

AZD2811 is a frozen sterile nanoparticle suspension for constitution for infusion. Each vial contains 10 mg/mL.

AZD2811 will be administered by IV infusion over 2 hours for doses up to and including 600 mg and by IV infusion over 4 hours for doses above 600 mg. AZD2811 will be given on Days 1 and 4 of each 28-day cycle.

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)




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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).


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

  2. 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

  3. 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)

  4. 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%.

  5. Overall Survival (OS) [ Time Frame: Up to 6 months ]
  6. Maximum plasma drug concentration after single dose (Cmax) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  7. Time to reach maximum plasma drug concentration (tmax) after single dose. [ Time Frame: Days 1 and 4 of Cycle 1 ]
  8. Area under the plasma concentration-time curve (AUC) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  9. Area under the 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 ]
  10. Terminal elimination half-life (t1/2λz) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  11. Clearance (CL) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  12. Volume of distribution (Vz) [ Time Frame: Days 1 and 4 of Cycle 1 ]
  13. 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.



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 vary between 1 to 5 weeks 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]); 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.

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
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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
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United States, Colorado
Research Site Recruiting
Denver, Colorado, United States, 80218
United States, Florida
Research Site Recruiting
Sarasota, Florida, United States, 34232
United States, Michigan
Research Site Recruiting
Detroit, Michigan, United States, 48201
United States, Oklahoma
Research Site Recruiting
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site Recruiting
Houston, Texas, United States, 77030
Research Site Not yet recruiting
San Antonio, Texas, United States, 78229
United States, Wisconsin
Research Site Recruiting
Milwaukee, Wisconsin, United States, 53051
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Will Donnellan, MD SCRI Development Innovations, LLC

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03217838     History of Changes
Other Study ID Numbers: D6130C00003
HEMREF 41 ( Other Identifier: Sarah Cannon Development Innovations, LLC )
First Posted: July 14, 2017    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
AZD2811
AZD1152
AZD1152 hQPA
barasertib
azacitidine
Vidaza

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors