E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Haematological Malignancies |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007051 |
E.1.2 | Term | Cancer (NOS) |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety and tolerability of AZD0466 in patients with advanced haematological malignancies |
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E.2.2 | Secondary objectives of the trial |
To characterize the pharmacokinetic (PK) profile of AZD0466 following intravenous administration (via PK profiles of the active moiety AZD4320 in plasma) [Core Module] To estimate the preliminary antitumor activity of AZD0466 [Module 1] To assess the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole [Module 2] |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subjects must be aged ≥18 years inclusive, at the time of signing the informed consent. In some countries parental consent may be required in addition to an assent form for patients who are 18 years of age. • Histologically confirmed acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) or intermediate or higher risk myelodysplastic syndrome (MDS; Part A only) for which there are limited treatment options known to provide clinical benefit. • Subjects must have received at least one prior line of therapy, and an established standard of care with proven benefit, and for which the patient is eligible, must not be available at the time of enrolment. • 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. • White blood cell count must be <10 x 10^9/L prior to the first dose in Cycle 1, Day 1. Treatment with hydroxyurea (AML) or high-dose steroids (ALL and leukaemia of ambiguous lineage) during screening and Cycle 1 to control white blood cell count is permitted. • 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, patients must fulfil protocol defined criteria. • Women of childbearing potential and men should use protocol defined contraceptive measures. |
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E.4 | Principal exclusion criteria |
• Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for Adverse Events Grade ≥2. Patients with Grade 2 neuropathy or Grade 2 alopecia are eligible. • Active idiopathic thrombocytopenic purpura. • Haemopoietic 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. The following are permitted: (a) topical steroids for GVHD; (b) systemic steroids for GVHD up to 2 weeks prior to the first dose of study treatment; (c) treatment with high-dose steroids (ALL and leukaemia of ambiguous lineage) for white blood cell count control is permitted during screening, and in Cycle 1 up to 4 days. • Active central nervous system (CNS) leukaemia/leptomeningeal disease/spinal cord compression. Patients 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. • 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; 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: subjects with 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 electrocardiograms (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 as 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); malignancy treated with curative intent and with no evidence of active disease present; 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; anticancer agents within ≤14 days or 5 half-lives prior to the first dose of study treatment; Treatment with high-dose steroids (ALL and leukaemia of ambiguous lineage) for white blood cell count control is permitted during screening, and in Cycle 1 up to 4 days; subjects can continue to receive hydroxyurea (AML) until the start of Cycle 2, and should be stopped once the white blood cell count falls <10 × 10^9/L; immunotherapies and cellular therapies within 4 weeks prior to the first dose of study treatment; investigational drugs within ≤14 days or 5 half-lives prior to the first dose of study treatment; major surgery ≤21 days, or minor surgical procedures ≤7 days, prior to the first dose of study treatment; prescription or non-prescription drugs or other products i.e., sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, reversible CYP3A inhibitors, and medications with known risk of Torsades de Pointe 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 14 days 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. • History of hypersensitivity to polyethylene glycol (PEG), PEGylated products or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [Core Module] • Changes from baseline in laboratory findings, physical examinations, performance status, electrocardiograms and vital signs [Core Module] • Dose-limiting toxicity [Module 1] • Maximum tolerated dose [Module 1] • Recommended Phase II dose [Module 1] |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Module 1 and Module 2: From Screening until post treatment follow-up (28 days after last dose) • Module 1: From Screening until post treatment follow-up (28 days after last dose); Module 2: From Screening until Day 19 • Day 1 to Day 35 of Cycle 1 (35-day Cycle) • Day 1 to Day 35 of Cycle 1 (35-day Cycle) • Day 1 to Day 35 of Cycle 1 (35-day Cycle) |
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E.5.2 | Secondary end point(s) |
• Plasma concentrations and derived PK parameters for total and released AZD4320 • Complete Response Rate (CR+CRi); Time to Response (TTR); Duration of Response (DoR); Overall Survival (OS) [Module 1] • Area under the plasma concentration-curve (AUC) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [Module 2]; Maximum observed plasma (peak) drug concentration (Cmax) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [Module 2] |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Module 1: Days 1 and 4, and days 8, 9, 10, 11 of Cycle 1; 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) • Module 1: Day 1 until post treatment follow-up (28 days after last dose) • 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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Korea, Republic of |
United States |
France |
Germany |
Italy |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last visit of the last subject in the study or last scheduled procedure shown in the Schedule of Activity for the last subject in the study globally. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |