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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03217838




Registration number
NCT03217838
Ethics application status
Date submitted
13/07/2017
Date registered
14/07/2017

Titles & IDs
Public title
Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticles as Monotherapy or in Combination in Acute Myeloid Leukemia Participants.
Scientific 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.
Secondary ID [1] 0 0
HEMREF 41
Secondary ID [2] 0 0
D6130C00003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AZD2811
Treatment: Drugs - Azacitidine
Treatment: Drugs - Venetoclax

Experimental: Group 1 Arm A (AZD2811 Dose 1) - 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.

Experimental: Group 1 Arm A (AZD2811 Dose 2) - 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.

Experimental: Group 1 Arm A (AZD2811 Dose 3) - 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.

Experimental: Group 1 Arm A (AZD2811 Dose 4) - 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.

Experimental: Group 1 Arm A (AZD2811 Dose 5) - 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.

Experimental: Group 1 Arm B (AZD2811 Dose 2) - 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.

Experimental: Group 1 Arm B (AZD2811 Dose 6) - 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.

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

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

Experimental: Group 2 Arm B (AZD2811 Dose 2 + Azacitidine 75 mg/m^2) - 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.

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

Experimental: Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 200 mg) - 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.

Experimental: Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 400 mg) - 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.


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

Treatment: Drugs: 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. 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.

Treatment: Drugs: 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 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Dose-limiting Toxicities (DLTs)
Timepoint [1] 0 0
Day 1 to Day 28 of first cycle
Primary outcome [2] 0 0
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Timepoint [2] 0 0
Day 1 through early termination of the study (approximately 42 months)
Primary outcome [3] 0 0
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Grade 4 TEAEs
Timepoint [3] 0 0
Day 1 through early termination of the study (approximately 42 months)
Secondary outcome [1] 0 0
Number of Participants With Total Complete Remission (CR)
Timepoint [1] 0 0
Day 1 through early termination of the study (approximately 42 months)
Secondary outcome [2] 0 0
Number of Participants With Overall Response Rate (ORR)
Timepoint [2] 0 0
Day 1 through early termination of the study (approximately 42 months)
Secondary outcome [3] 0 0
Number of Participants With Partial Remission (PR)
Timepoint [3] 0 0
Day 1 through early termination of the study (approximately 42 months)
Secondary outcome [4] 0 0
Number of Participants With >50% Change in Bone Marrow Blasts from Baseline in Participants With AML
Timepoint [4] 0 0
Baseline (Day 1), Cycle 1 Day 22, Cycle 2 Day 22, Cycle 4 Day 22, and end of treatment (approximately 42 months)

Eligibility
Key inclusion criteria
Inclusion criteria

1. AML participants who have either: (a) relapsed or are refractory to standard therapies (the participant 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 participants only i.e. inclusion criteria 1(b) may only be used to enrol a participant into Groups 1 and 2; previously untreated AML participants may not enrol into Group 3 unless they fulfil inclusion criteria 1(a) above).

Participants 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 participant unsuitable for intensive induction therapy. This must be documented by the study monitor.
2. AML participants 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:

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.
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 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.
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 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
2. 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 .
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); 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.
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 participants) or >470 ms (for female participants) on screening electrocardiogram (ECG).
6. 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..
7. Participants with a known hypersensitivity to azacitidine or mannitol (HMA combination participants 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. Participants who are anti-HBc positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrolment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive will be excluded.
2. Participants 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. White blood cell (WBC) count > 25,000 cells/mm^3 (25 x 10^9/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. Participant consumed grapefruit, grapefruit products, Seville oranges (including marmalades containing Seville oranges) or star fruit within 3 days before the initiation of venetoclax.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
31/07/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
25/03/2021
Sample size
Target
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Michigan
Country [4] 0 0
United States of America
State/province [4] 0 0
North Carolina
Country [5] 0 0
United States of America
State/province [5] 0 0
Ohio
Country [6] 0 0
United States of America
State/province [6] 0 0
Oklahoma
Country [7] 0 0
United States of America
State/province [7] 0 0
Tennessee
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Wisconsin

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Howard Burris, MD
Address 0 0
SCRI Development Innovations, LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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.
When will data be available (start and end dates)?
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.
Available to whom?
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.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03217838