| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment Naïve or Relapsed/Refractory Acute Myeloid Leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Blood cancer [(Acute Myeloid Leukemia (AML)] in which there are too many immature blood-forming cells in the blood and bone marrow. In AML, these blood cells do not mature and so become too numerous. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The study will be conducted in two parts, designated A and B.
The primary objective of Part A is to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of AZD2811 monotherapy or with combination agent(s) in patients with relapsed/refractory acute myeloid leukemia (AML) or treatment-naïve patients not eligible for intensive induction therapy. Part A is the dose escalation segment. In Arm 1, Part A patients will receive a 2- or 4-hour IV infusion of AZD2811 on Days 1 and 4 of each 28-day cycle. In Arm 2, Part A patients will receive AZD2811 on Days 1, 4, 15, and 18 of each 28-day cycle.
The primary objective of Part B is to assess the effect of AZD2811 monotherapy or with combination agent(s) on the rate of complete remission (total CR) defined as complete remission (CR) + complete remission with incomplete recovery (CRi) in patients with treatment-naïve AML not eligible for intensive induction therapy. Part B is the dose expansion segment of the study. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives of the trial include the following:
1. Characterise the pharmacokinetics (PK) of total AZD2811 monotherapy or with combination agent(s) in whole blood in AML patients.
2. Characterise the PK of venetoclax when administered in combination with AZD2811 (venetoclax combination arm [Part A only]).
3. Determine the biological effective dose (BED) of AZD2811 monotherapy or with combination agent(s) in AML patients in Part A.
4. Evaluate the effect of AZD2811 monotherapy or with combination agent(s) on the levels of leukemic blasts in the blood and marrow samples by standard of care analysis (morphology, flow cytometry, cytogenetics, molecular genetics) including biomarkers of activity.
5. Assess the effect of AZD2811 monotherapy or with combination agent(s) on overall response rate (ORR, [CR + CRi + PR]), CR, CRi, partial remission (PR) and overall survival (OS) at 6 months. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 Cockcroft-Gault method, OR 24-hour measured urine creatinine clearance ≥ 50 mL/min. Patients enrolled in the venetoclax combination part with a 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 TLS when initiating
treatment with venetoclax.
6. Other comorbidity that the Investigator judges incompatible with intensive remission induction chemotherapy, which must be documented
by the study monitor.
7. Females should be using adequate contraception, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
‒ Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
‒ Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
8. Sexually active male patients should be willing to use barrier contraception i.e., condoms. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential, unless the male patient is abstaining from sexual intercourse.
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| E.4 | Principal exclusion criteria |
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 disease). Patients with a rash that is biopsy-proven leukaemia or with pressure ulcers are not excluded. Patients with petechiae from thrombocytopenia or patients with drug related rashes that are improving are not excluded.
7. Patients with a known hypersensitivity to azacitidine or mannitol (HMA combination patients 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:
‒ Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before enrolment. Those who are hepatitis B surface antigen positive or hepatitis B polymerase chain reaction (PCR) positive will be excluded.
‒ Subjects 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. WBC count ≤ 25,000 cells/mm³ (25 x 10ꝰ/L); use of leukapheresis or hydroxyurea (48 hours) before venetoclax initiation is allowed to achieve this entry criterion.
2. AML with known active central nervous system involvement.
3. Chronic respiratory disease that requires continuous oxygen use.
4. Previous venetoclax exposure that ended due to venetoclax toxicity.
5. In addition to strong CYP3A inhibitor/inducers, moderate CYP3A inhibitor/inducers and P-gP inhibitors that cannot be discontinued prior to Day 1 of dosing and withheld throughout the first 4 weeks of study start. Washout periods should be a minimum of 5 half-lives depending on the medication.
6. Patient consumed grapefruit, grapefruit products, Seville oranges (including marmalades containing Seville oranges) or star fruit within 3 days before the initiation of venetoclax. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: The primary end points for determining maximum tolerated dose (MTD) are the incidences of dose-limiting toxicities (DLTs), adverse events (AEs) and abnormal laboratory results.
Part B: The primary end point for preliminary assessment of anti-tumour activity will be total complete remission (CR + CRi). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: The incidences of dose-limiting toxicities (DLTs), adverse events (AEs), and abnormal laboratory results will be assessed from the first day of drug administration through Cycle 1 (28 days).
Part B: Anti-tumour activity will be assessed for up to 6 months. |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints in Part A of the study include:
Tumour Response and Survival
1. Overall Response Rate (ORR), defined as the sum of CR + CRi + PR
2. Complete Remission (CR)
3. Complete Remission with incomplete recovery (CRi)
4. Partial Remission (PR)
5. Overall Survival (OS)
The following Pharmacokinetic (PK) parameters will be calculated in Part A for AZD2811:
6. Cycle 1, Days 1 and 4: maximum blood drug concentration after single dose (Cmax), time to reach maximum concentration (tmax), area under the plasma concentration-time curve (AUC), area under the plasma concentration-time curve from zero to the time of last measurable concentration [AUC(0-t)], terminal elimination half-life (t1/2λz), clearance (CL), and volume of distribution (Vz).
7. For Part A Arm 2 and Part B, only blood AZD2811 concentrations will be reported. Summary PK parameters will not be derived. The following PK parameters will be calculated in Part A for venetoclax data permitting:
8. Cycle 1 Day 4: Cmax, tmax, and AUC(0-t). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A
Tumour Response and Survival
A mandatory bone marrow aspirate/biopsy will be collected at screening, after Cycle 1, and after Cycle 2 and then every 2 cycles until remission is documented. Thereafter, bone marrow should be assessed for response when there is any suspicion of relapse, peripheral blood assessment shows disease progression, or at the discretion of the Investigator.
Pharmacokinetics
Venous blood samples (2 mL) for determination of concentrations of total and released AZD2811 in blood will be taken at the following times. The date and actual time of collection of each sample will be recorded.
Cycle 1 Day 1: Pre-dose, and 1, 2, 4, 6, 8, and 24 hours after dosing.
Cycle 1 Days 4-22: Pre-dose, and 1, 2, 4, 6, 8, 48, 96, 360, 528 hours after dosing. |
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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 | No |
| 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 | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
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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
|
| The end of the trial is defined as the last visit of the last subject. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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