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

NCT03217838 | Terminated Phase 1 FDA Drug

• 2 other identifiers: D6130C00003HEMREF 41
• Study Type: interventional
• Target: 50
• Locations: 2 countries
• Sites: 11

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) participants or treatment-naïve AML participants not eligible for intensive induction therapy. In addition, the study will explore the potential clinical activity by assessing anti-tumour activity in participants. The study was terminated early as a result of AstraZeneca's strategic review across the AZD2811 programme. Part A data were collected for initial cohorts; the MTD/recommended Phase 2 dose (RP2D) dose and schedule of AZD2811 monotherapy or with combination agents were not determined. Part B of the study was not initiated

Conditions

Acute Myeloid Leukaemia

Keywords

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

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Dose-limiting Toxicities (DLTs)

  A DLT was defined as any adverse event (AE) not related to the underlying leukaemia requiring treatment interruption for \> 21 days, any Grade 5 AE, Grade 4 neutropenia or thrombocytopenia lasting \>= 42 days from start of cycle in absence of evidence of active leukaemia, any \>= Grade 3 non-haematological AE (except Grade 3 nausea, vomiting, mucositis, stomatitis or diarrhoea that was controlled within 4 days and Grade 3 elevations in alanine aminotransferase/ aspartate aminotransferase that return to meet initial eligibility criteria within 7 days of study drug interruption), or any other clinically significant and/or unacceptable AE that does not respond to supportive care, results in a disruption of dosing schedule for \> 7 days, or was judged as a DLT by Investigator in collaboration with the Medical Monitor. An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

  Day 1 to Day 28 of first cycle

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

  An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. There will be no updated results for this outcome measures at the time of end of study.

  Day 1 through early termination of the study (approximately 42 months)

• Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Grade 4 TEAEs

  Participants with abnormal clinical laboratory parameters reported as Grade 4 TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, and urinalysis. hematology, coagulation, chemistry, and urinalysis parameters over time are reported.

  Day 1 through early termination of the study (approximately 42 months)

Secondary Outcomes (4)

• Number of Participants With Total Complete Remission (CR)

  Day 1 through early termination of the study (approximately 42 months)

• Number of Participants With Overall Response Rate (ORR)

  Day 1 through early termination of the study (approximately 42 months)

• Number of Participants With Partial Remission (PR)

  Day 1 through early termination of the study (approximately 42 months)

• Number of Participants With >50% Change in Bone Marrow Blasts from Baseline in Participants With AML

  Baseline (Day 1), Cycle 1 Day 22, Cycle 2 Day 22, Cycle 4 Day 22, and end of treatment (approximately 42 months)

Study Arms (13)

Group 1 Arm A (AZD2811 Dose 1)

EXPERIMENTAL

Participants with AML will receive intevenous (IV) infusion of AZD2811 Dose 1 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 1 Arm A (AZD2811 Dose 2)

EXPERIMENTAL

Participants with AML and myelodysplastic syndrome (MDS) will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 1 Arm A (AZD2811 Dose 3)

EXPERIMENTAL

Participants with AML and MDS will receive IV infusion of AZD2811 Dose 3 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 1 Arm A (AZD2811 Dose 4)

EXPERIMENTAL

Participants with AML and MDS will receive IV infusion of AZD2811 Dose 4 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 1 Arm A (AZD2811 Dose 5)

EXPERIMENTAL

Participants with AML will receive IV infusion of AZD2811 Dose 5 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 1 Arm B (AZD2811 Dose 2)

EXPERIMENTAL

Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1, 4, 15, and 18 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 1 Arm B (AZD2811 Dose 6)

EXPERIMENTAL

Participants with AML will receive IV infusion of AZD2811 Dose 6 on Days 1, 4, 15, and 18 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811

Group 2 Arm A (AZD2811 Dose 3 + Azacitidine 75 mg/m^2)

EXPERIMENTAL

Participants with AML and MDS will receive Azacitidine 75 mg/m\^2 of body surface area (BSA) by subcutaneous (SC) injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 3 on Days 1 and 4 of each 28-day cycle. Participants will receive the study treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811; Drug: Azacitidine

Group 2 Arm A (AZD2811 Dose 4 + Azacitidine 75 mg/m^2)

EXPERIMENTAL

Participants with AML will receive Azacitidine 75 mg/m\^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 4 on Days 1 and 4 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811; Drug: Azacitidine

Group 2 Arm B (AZD2811 Dose 2 + Azacitidine 75 mg/m^2)

EXPERIMENTAL

Participants with AML will receive Azacitidine 75 mg/m\^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 2 on Days 1, 4, 15, and 18 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811; Drug: Azacitidine

Group 2 Arm B (AZD2811 Dose 6 + Azacitidine 75 mg/m^2)

EXPERIMENTAL

Participants with AML will receive Azacitidine 75 mg/m\^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 6 on Days 1, 4, 15, and 18 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811; Drug: Azacitidine

Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 200 mg)

EXPERIMENTAL

Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle and venetoclax 100 mg orally (PO) on Day 1 and 200 mg PO from Days 2 to 28 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811; Drug: Venetoclax

Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 400 mg)

EXPERIMENTAL

Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle and venetoclax 100 mg orally (PO) on Day 1, 200 mg PO on Day 2, and 400 mg PO from Days 3 to 28 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.

Drug: AZD2811; Drug: Venetoclax

Interventions

AZD2811 DRUG

AZD2811 will be administered by IV infusion with the specified dose level as reported in arms in 28-day cycles.

Also known as: AZD1152 hQPA, AZD1152 hydroxyl-quinazoline pyrazole anilide

Group 1 Arm A (AZD2811 Dose 1); Group 1 Arm A (AZD2811 Dose 2); Group 1 Arm A (AZD2811 Dose 3); Group 1 Arm A (AZD2811 Dose 4); Group 1 Arm A (AZD2811 Dose 5); Group 1 Arm B (AZD2811 Dose 2); Group 1 Arm B (AZD2811 Dose 6); Group 2 Arm A (AZD2811 Dose 3 + Azacitidine 75 mg/m^2); Group 2 Arm A (AZD2811 Dose 4 + Azacitidine 75 mg/m^2); Group 2 Arm B (AZD2811 Dose 2 + Azacitidine 75 mg/m^2); Group 2 Arm B (AZD2811 Dose 6 + Azacitidine 75 mg/m^2); Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 200 mg); Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 400 mg)

Azacitidine DRUG

Azacitidine is supplied in vials of 25 mg/mL powder for suspension for injection. After reconstitution, each vial contains a maximum of 100 mg. Participants should be pre-medicated for nausea and vomiting according to institutional standards before receiving azacitidine. Participants 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.

Also known as: Vidaza (TM)

Group 2 Arm A (AZD2811 Dose 3 + Azacitidine 75 mg/m^2); Group 2 Arm A (AZD2811 Dose 4 + Azacitidine 75 mg/m^2); Group 2 Arm B (AZD2811 Dose 2 + Azacitidine 75 mg/m^2); Group 2 Arm B (AZD2811 Dose 6 + Azacitidine 75 mg/m^2)

Venetoclax DRUG

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 of each 28-day cycle or 100 mg orally (PO) on Day 1, 200 mg PO on Day 2, and 400 mg PO from Days 3 to 28 of each 28-day cycle. The third participant in Group 3 Arm A will only be enrolled after the first 2 participants will receive ≥2 weeks of treatment and have shown no evidence of toxicity observed to be compatible with a DLT.

Also known as: Venclexta (TM)

Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 200 mg); Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 400 mg)

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants are unsuitable for intensive induction therapy if they are:
• years or
• 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 participant unsuitable for intensive induction therapy. This must be documented by the study monitor.
• AML participants who are unlikely to demonstrate rapid progression such that they would be unable to complete the first cycle of therapy.
• Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses.
• Aged at least 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Prior treatment with hydroxyurea (up to 24 hours before study treatment) is allowed
• Adequate organ system function as outlined below:
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤1.5 x upper limit of normal (ULN) Total bilirubin ≤1.5 x ULN. Participants 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.
• Participants enrolled in the venetoclax combination part with a creatinine clearance (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 tumour lysis syndrome (TLS) when initiating treatment with venetoclax.
• 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.
• Sexually active male participants should be willing to use barrier contraception i.e., condoms. Female partners of male participants should also use a highly effective form of contraception if they are of childbearing potential, unless the male participant is abstaining from sexual intercourse.

You may not qualify if:

• 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 clinical study protocol.
• 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.
• Participants 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
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment .
• Presence of, or history of leptomeningeal disease.
• 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); participants 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.
• 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 participants) or \>470 ms (for female participants) on screening electrocardiogram (ECG).
• Active non-infectious skin disease (including rash, dermatitis, or psoriasis, but excluding stable plaque psoriasis from the definition of active disease). Participants with a rash that is biopsy-proven leukaemia or with pressure ulcers are not excluded. Participants with petechiae from thrombocytopenia or participants with drug related rashes that are improving are not excluded..
• Participants with a known hypersensitivity to azacitidine or mannitol (HMA combination participants only).
• 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.
• Known history of infection with human immunodeficiency virus (HIV)

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (11)

Research Site

Denver, Colorado, 80218, United States

Location

Research Site

Sarasota, Florida, 34232, United States

Location

Research Site

Detroit, Michigan, 48201, United States

Location

Research Site

Charlotte, North Carolina, 28204, United States

Location

Research Site

Canton, Ohio, 44718, United States

Location

Research Site

Oklahoma City, Oklahoma, 73104, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Dallas, Texas, 75246, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Milwaukee, Wisconsin, 53226, United States

Location

Research Site

Melbourne, 3004, Australia

Location

Related Links

• Related Info

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

AZD2811; Azacitidine; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Howard Burris, MD

  SCRI Development Innovations, LLC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2017
• First Posted: July 14, 2017
• Study Start: July 31, 2017
• Primary Completion: March 25, 2021
• Study Completion: March 25, 2021
• Last Updated: April 5, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• 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.

Locations

AU (1); US (10)