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Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04865419
Recruitment Status : Recruiting
First Posted : April 29, 2021
Last Update Posted : September 8, 2022
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE April 26, 2021
First Posted Date  ICMJE April 29, 2021
Last Update Posted Date September 8, 2022
Actual Study Start Date  ICMJE June 11, 2021
Estimated Primary Completion Date June 14, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 26, 2021)
  • Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Module 1] [ Time Frame: Until 28 days after last dose (Upto 3.5 Years) ]
    Assessment of the safety and tolerability of AZD0466 in participants with advanced haematological malignancies.
  • Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Module 2] [ Time Frame: Until Day 19 ]
    Assessment of the safety and tolerability of AZD0466 in participants with advanced haematological malignancies.
  • Number of participants with Dose-limiting toxicity (DLT) [Module 1] [ Time Frame: 35 days ]
    Assessment of DLT to evaluate safety and tolerability of AZD0466 in participants with advanced haematological malignancies.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 9, 2021)
  • Module 1: Complete Response Rate (CR+CRi) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years) ]
    To estimate the preliminary anti-tumor activity of AZD0466 by assessment of complete response rate [complete remission+complete remission with incomplete recovery (CR+CRi)] defined as the proportion of participants with a best response of CR or CRi.
  • Module 1: Time to Response (TTR) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years) ]
    To estimate the preliminary antitumor activity of AZD0466 by assessment of TTR defined as the time from date of first dose until the date of first documented CR or CRi.
  • Module 1: Duration of Response (DoR) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years) ]
    To estimate the preliminary antitumor activity of AZD0466 by assessment of DoR defined as the time from the date of first documented response (CR or CRi) until date of documented progression, relapse or failure or death due to any cause.
  • Module 1: Overall Survival (OS) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) and survival follow-up (every month after last dose) (up to 3.5 Years) ]
    To estimate preliminary anti-tumor activity of AZD0466 by assessment of OS defined as time from date of first dose until the date of death due to any cause.
  • Module 2: Area under the plasma concentration-curve (AUC) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [ Time Frame: Cycle 1 Days 1, 2, 3, 4, 8 and days 15, 16, 17, 18, 19, and Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years) ]
    Assessment of AUC to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.
  • Module 2: Maximum observed plasma (peak) drug concentration (Cmax) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [ Time Frame: Cycle 1: Days 1, 2, 3, 4, 8 and days 15, 16, 17, 18, 19, and Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years) ]
    Assessment of Cmax to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.
  • Module 1 and Module 2: Plasma concentration of AZD4320 [ Time Frame: Module 1: Cycle 1 Days 1-30 (Cycle length 21 days) to Cycle 3 Days 1-28, and beyond (Cycle length 28 days); Module 2: Cycle 1 Days 1-8, Days 15-19 (Cycle length 21 days), Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years) ]
    Assessment of AZD4320 to characterise the PK profile of AZD0466 following intravenous administration (via PK profiles of the active moiety AZD4320 in plasma).
Original Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2021)
  • Module 1: Complete Response Rate (CR+CRi) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (upto 3.5 Years) ]
    To estimate the preliminary anti-tumor activity of AZD0466 by assessment of complete response rate [complete remission+complete remission with incomplete recovery (CR+CRi)] defined as the proportion of participants with a best response of CR or CRi.
  • Module 1: Time to Response (TTR) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (upto 3.5 Years) ]
    To estimate the preliminary antitumor activity of AZD0466 by assessment of TTR defined as the time from date of first dose until the date of first documented CR or CRi.
  • Module 1: Duration of Response (DoR) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (upto 3.5 Years) ]
    To estimate the preliminary antitumor activity of AZD0466 by assessment of DoR defined as the time from the date of first documented response (CR or CRi) until date of documented progression, relapse or failure or death due to any cause.
  • Module 1: Overall Survival (OS) [ Time Frame: Day 1 until post treatment follow-up (28 days after last dose) (upto 3.5 Years) ]
    To estimate preliminary anti-tumor activity of AZD0466 by assessment of OS defined as time from date of first dose until the date of death due to any cause.
  • Module 2: Area under the plasma concentration-curve (AUC) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [ Time Frame: Days 1, 2, 3, 4, and 8 (Period 1) and days 15, 16, 17, 18, 19 (Period 3) during Cycle 1 (21 days) ]
    Assessment of AUC to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.
  • Module 2: Maximum observed plasma (peak) drug concentration (Cmax) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [ Time Frame: Days 1, 2, 3, 4, and 8 (Period 1) and days 15, 16, 17, 18, 19 (Period 3) during Cycle 1 (21 days) ]
    Assessment of Cmax to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.
  • Plasma concentration of AZD4320 [ Time Frame: Days 1 and 4, and days 8, 9, 10, 11 of Cycle 1 (21 days); Module 2: Days 1, 2, 3, 4, and 8 (Period 1) and days 15, 16, 17, 18, 19 (Period 3) during Cycle 1 (21 days) ]
    Assessment of AZD4320 to characterise the PK profile of AZD0466 following intravenous administration (via PK profiles of the active moiety AZD4320 in plasma).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies
Official Title  ICMJE A Modular Phase I/II, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies
Brief Summary The purpose of the study is to the evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of AZD0466 as monotherapy in partciapants with advanced haematological malignancies and also to assess drug-drug interaction (DDI) potential between AZD0466 and the azole antifungal voriconazole.
Detailed Description

The study consists of 2 individual modules as: Module 1 (AZD0466 monotherapy), and Module 2 (DDI study of AZD0466 with voriconazole).

Eligible participants will be assigned to study treatments across Modules 1 and 2.

  1. Module 1: AZD0466 monotherapy will include 2 parts- Part A dose escalation cohorts and Part B dose expansion cohorts. Initiation of Part B will depend on the evaluation of safety, tolerability, and PK in Part A.
  2. Module 2: AZD0466 and voriconazole DDI study.

All participants will receive AZD0466, and administration will continue until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment.

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 Haematological Malignancies
Intervention  ICMJE
  • Drug: AZD0466
    AZD0466 powder for concentrate for solution for infusion will be administered by IV infusion.
  • Drug: Voriconazole
    Voriconazole film-coated tablet will be administered orally.
Study Arms  ICMJE
  • Experimental: Module 1: AZD0466 monotherapy
    Participants will receive intravenous infusion of AZD0466 monotherapy once weekly during Cycle 1 (35 days), Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.
    Intervention: Drug: AZD0466
  • Experimental: Module 2: AZD0466 + Voriconazole
    Participants may receive IV infusion of AZD0466 in combination with or without voriconazole during Cycle 1 (21 days), and Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.
    Interventions:
    • Drug: AZD0466
    • Drug: Voriconazole
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 14, 2021)
141
Original Estimated Enrollment  ICMJE
 (submitted: April 26, 2021)
160
Estimated Study Completion Date  ICMJE June 14, 2024
Estimated Primary Completion Date June 14, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) for which there are limited treatment options known to provide clinical benefit.
  • Eastern cooperative oncology group performance status ≤2. Performance status must not have deteriorated by ≥2 levels within 2 weeks after providing informed consent.
  • Predicted life expectancy ≥8 weeks.
  • Adequate organ function at screening as per the protocol defined criteria.
  • Adequate cardiac function as demonstrated by LVEF > 50% on screening cardiac multigated acquisition, magnetic resonance image or echocardiogram.
  • Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study treatment and admission to the hospital, when required, for administration of study treatment and monitoring.
  • For inclusion in the genetic component of the study, participants must fulfil protocol defined criteria.
  • White blood cell count must be <10 x 10^9/L. Treatment with hydroxyurea during screening and Cycle 1 to achieve this level is permitted.
  • Women of childbearing potential and men should use protocol defined contraceptive measures.

Exclusion Criteria:

  • Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for Adverse Events Grade ≥2. Participants with Grade 2 neuropathy or Grade 2 alopecia are eligible.
  • Active idiopathic thrombocytopenic purpura.
  • Stem cell transplant < 100 days prior to the first dose of study treatment.
  • Immunosuppression for graft versus host disease (GVHD) or GVHD prophylaxis within 4 weeks prior to the first dose of study treatment.
  • Active central nervous system (CNS) leukaemia/leptomeningeal disease/spinal cord compression. Participants who have a history of CNS leukaemia must be free of CNS leukaemia for >30 days prior to the first dose of study treatment, and the most recent 2 lumbar punctures must be negative for leukaemic cells, to be eligible.
  • Known uncontrolled infection with cytomegalovirus (CMV) infection (positive CMV Immunoglobulin M (IgM) and/or positive polymerase chain reaction (PCR) result).
  • Active infection including human immunodeficiency virus, Hepatitis B, Hepatitis C, or severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).
  • As judged by the Investigator: any evidence of severe or uncontrolled systemic diseases, (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]); current unstable or uncompensated respiratory or cardiac conditions; Uncontrolled hypertension; history of, or active, bleeding diatheses (eg, haemophilia or von Willebrand disease); uncontrolled active systemic fungal, bacterial, or other infection.
  • Any of the given cardiac criteria: history of myocarditis within one year of study entry, or heart failure New York Heart Association Functional Classification Class 3 or 4; mean resting corrected QT interval (QTcF) ≥470 msec obtained from 3 electrocardiogram (ECGs), in the absence of a cardiac pacemaker; abnormalities in rhythm, conduction or morphology of resting ECG; any factors that increase the risk of QTc prolongation or risk of arrhythmic events such congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age.
  • History of another life-threatening malignancy ≤2 years prior to first dose of study treatment. The following are permitted: myelodysplastic syndrome or myeloproliferative neoplasm (including chronic myelomonocytic leukaemia [CMML]); malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and considered to be at low risk of recurrence by the treating physician; adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer; adequately treated carcinoma in situ without current evidence of disease.
  • Any of the mentioned procedures or conditions currently or in the 6 months prior to the first dose of study treatment: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.
  • Treatment with any of the mentioned therapy: radiotherapy less than 3 weeks prior to first study treatment; chemotherapy within ≤14 days or 5 half-lives prior to the first dose of study treatment. Treatment with high-dose steroids for primary malignancy control is permitted but must be discontinued at least 2 days prior to the first dose of study treatment. Treatment with hydroxyurea is permitted; immunotherapies and cellular therapies within 4 weeks prior to the first dose of study treatment; investigational drugs within ≤14 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment; major surgery (excluding placement of vascular access) ≤21 days, or minor surgical procedures ≤7 days, prior to the first dose of study treatment. No waiting is required mentioned implantable port or catheter placement; prescription or non-prescription drugs or other products known to be sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, or reversible moderate or strong CYP3A inhibitors, which cannot be discontinued within 5 half-lives prior to the first dose of study treatment and withheld throughout the study until 14 days after the last dose of AZD0466; moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5 half-lives plus of the specific drug 12 days of the drug prior to the first dose of study treatment and withheld until 14 days after the last dose of AZD0466; concurrent anti-coagulation therapy, including aspirin and heparin, which cannot be stopped; medications with known risk of Torsades de Pointes which cannot be discontinued within 5 half-lives of the first dose of study treatment and withheld until 14 days after the last dose of AZD0466; IV anti infection treatment within 14 days before first dose of study treatment.
  • History of hypersensitivity to polyethylene glycol (PEG), PEGylated products or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic.

Module 2:

• Patients for whom treatment with voriconazole is contraindicated per the local prescribing information must not enter the study.

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: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Australia,   France,   Germany,   Italy,   Korea, Republic of,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04865419
Other Study ID Numbers  ICMJE D8241C00001
Has Data Monitoring Committee Yes
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 requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

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 refer 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 patientlevel 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
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Dr. Marina Konopleva, MD, PhD The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, Texas 77030 United States of America
PRS Account AstraZeneca
Verification Date September 2022

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