Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 as Monotherapy or in Combination in Myeloid Leukemia Patients.
- Conditions
- Treatment Naïve or Relapsed/Refractory Acute Myeloid LeukemiaTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-003857-73-GB
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Not specified
- Target Recruitment
- 130
Patients must meet all of the following criteria:
Part A Inclusion Criteria (dose escalation)
1. AML patients who have relapsed or are refractory to standard therapies (all patients)
2. AML patients who are unlikely to demonstrate rapid progression such that they would be unable to complete the first cycle of therapy (all patients)
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 (monotherapy and HMA combination patients):
• =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 Inclusion Criterion (dose expansion)
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
Inclusion Criteria for All Patients
1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses. If a patient declines to participate in any genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study.
2. Aged = 18 years
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 (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 Coc
Patients must not enter the study if any of the following exclusion criteria are fulfilled:
1. Treatment with:
? Any investigational agents, experimental antibody or antibody drug conjugates, or study drugs from a previous clinical study within 3-4 weeks prior to the first dose of study treatment in this study.
? Any other chemotherapy, immunotherapy or anticancer agents < 2 weeks of the first dose of study treatment.
? Any haematopoietic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) < 7 days of the first dose of AZD2811 monotherapy or with combination agent(s) or pegylated G-CSF (pegfilgrastim) or darbepoetin < 14 days of the first dose of study treatment.
? Prescription (Rx) or non-Rx 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 should be a minimum of 5 half-lives depending on the medication.
? Patients who have undergone allogeneic stem cell transplant < 12 months are excluded. If allogeneic transplant was > 12 months ago, they are not excluded if they are off all immunosuppression and have no signs or symptoms of active graft vs. host disease.
? Major surgery (excluding placement of vascular access) < 4 weeks of the first dose of study treatment.
2. Any unresolved toxicities (except alopecia) from prior therapy greater than CTCAE Grade 1.
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); patients 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 clear evidence would indicate that despite the clinical symptoms no infection took place.
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 di
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method