| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myelogenous Leukemia (AML) |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with Acute Myelogenous Leukemia (AML) who have either relapsed after previous induction chemotherapy or are ineligible for initial or further induction chemotherapy. |
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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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
In Part 1, the primary objectives are: To examine the safety and tolerability of AKN-028 and to determine the recommended Phase 2 dose (RPTD) of AKN-028 for further evaluation in Part 2 in the same patient population; and To characterize the pharmacokinetic (PK) parameters for AKN-028 in patients with AML.
In Part 2, the primary objective is to determine the overall remission rate (OR) defined as CR (complete remission) + CRi (CR with incomplete recovery) + PR (partial remission)
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| E.2.2 | Secondary objectives of the trial |
Exploratory Objectives:
In Part 1 and Part 2, the exploratory objectives of the study are: To examine the overall survival of patients with AML treated with AKN-028; To determine the clinical activity of AKN-028:
o complete remission (CR) rate;
o morphologic leukemia free state (MLFS);
o duration of response assessed by leukemia-free survival (LFS); To examine biological response to AKN-028, including effects on:
o peripheral and bone marrow blast counts;
o neutrophil and platelet counts;
o bone marrow cellularity;
o cytogenetics;
o disease-related comorbidities, such as independence from packed red blood cell (RBC) transfusions or platelet transfusions as well as infectious complications. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in Part 1 or Part 2 of the study only if they meet all of the following criteria:
1. Provide written informed consent prior to Screening;
2. Male or female patients, age ≥ 18 years;
3. For females of childbearing potential, a negative urine pregnancy test must be obtained prior to administration of AKN-028. Female patients, of childbearing potential, must use an Investigator-approved method of birth control (i.e. oral contraception, barrier contraception, intrauterine device) throughout the course of the study and for 30 days after the last dose of study drug. Male patients with female partners of childbearing potential must also use an Investigator-approved method of birth control throughout the course of the study and for 30 days after the last dose of study drug.;
4. Confirmed diagnosis of AML (≥ 20% blasts in bone marrow and/or peripheral blood) according to World Health Organisation (WHO) classification and meeting at least one of the following: Newly diagnosed AML, but according to the clinical judgment of the principal investigator, patient is not a candidate for induction chemotherapy because of age, comorbidity, performance status, or other factors; AML in first relapse with WBC < 60,000/mm3 and ineligible for further intensive induction chemotherapy; AML in second relapse with low peripheral blast count (<10,000/mm3) and with WBC < 60,000/mm3 and ineligible for intensive induction chemotherapy; Primary refractory disease, here defined as patients with AML not having achieved CR following up to 2 courses of chemotherapy for enrollment in Part 1, and patients with AML refractory following only one course of chemotherapy for enrollment in Part 2;
Note: Severe neutropenia per se (up to Grade 4) should be accepted if it is likely to be related to the AML. However, the severe neutropenia may be due to the recently administered chemotherapy (e.g. cytarabin). It may be prudent to perform a new bone marrow examination. In case the marrow is hypoplastic (due to cytarabin) the screening should be postponed and G-CSF should be administered for a short period and then the patient should be re-evaluated. In case the bone marrow is not hypoplastic but rather infiltrated with AML cells the patient can be screened.
5. Performance status of 0-3 on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale (Appendix 1);
6. Adequate organ function, including the following: Serum creatinine ≤ 2.0 mg/dL (176.8 mMol/L) during screening; Aspartate aminotransferase (AST) and ALT ≤ 2x the upper limits of normal (ULN) during screening; Total bilirubin 1.5 x ULN during screening. |
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
Part 1 or Part 2 Exclusions:
1. Patients who are candidates for induction chemotherapy for AML;
2. Total WBC count ≥ 60,000 mm3;
3. Evidence of active central nervous system (CNS) leukemia;
4. Evidence of blast-phase CML;
5. Histological or cytogenetic diagnosis of AML with M3 subtype (Acute Promyelocytic Leukemia);
6. Lack of recovery of non-hematological toxicity from systemic therapy for the underlying hematologic condition;
7. Previous or concurrent malignancy except non-invasive non-melanoma skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively, and without evidence of recurrence for at least 2 years prior to study entry, (this exclusion does not refer to the disease [AML] under study);
8. Uncontrolled systemic infection (viral, bacterial, or fungal);
9. Uncontrolled disseminated intravascular coagulation;
10. Known positive serology for human immunodeficiency virus;
11. Clinically significant cardiac dysfunction (New York Heart Association Class 3 or 4) at the time of screening, or a history of myocardial infarction or heart failure within 3 months preceding the first dose of AKN-028;
12. Chronic Graft versus Host Disease (GVHD) with the exception of mild (Grade 1) skin or oral GVHD;
13. Major surgery within the 28 days preceding the first dose of AKN-028;
14. Concomitant administration of any other anti-leukemia or anti-neoplastic therapy (during the screening period, hydroxyurea is allowed for ≤ 7 days before Cycle 1 as well as ≤ 7 days in between cycles);
15. Concomitant treatment with immunotherapy, or any other investigational agent within 28 days preceding the first dose of AKN-028, or lack of recovery from toxicity of such treatment;
16. Active autoimmune disease requiring immunosuppressive therapy;
17. Radiotherapy, or lack of recovery of any radiotherapy-related acute toxicity, within the 28 days preceding the first dose of AKN-028;
18. Previous treatment in any clinical study with AKN-028, any other FLT3 inhibitor, or any other c-KIT inhibitor;
19. Female patients who are pregnant or breast-feeding;
20. Male, or female patients of childbearing potential, unwilling to use an approved, effective means of contraception (e.g., oral contraception, barrier contraception, intrauterine device) in accordance with the investigator’s standards;
21. Known current drug or alcohol abuse;
22. Active viral Hepatitis B and /or C;
23. Other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that, in the opinion of the investigator, may compromise the safety of the patient during the study, affect the patient’s ability to complete the study, or interfere with interpretation of study results;
24. Any condition, which is judged by the Investigator to be inappropriate for study participation, including an inability to communicate or cooperate with the Investigator and the requirements of this study.
Part 2 Only Exclusions:
25. AML secondary to previous malignant hematological disease, e.g. myelodysplastic syndrome, myeloproliferative neoplasms;
26. If 50% or more of cells in 2 or more myeloid lineage are dysplastic (AML with myelodysplasia related changes);
27. Primary refractory disease, defined as any patient not having achieved CR following ≥2 courses of standard chemotherapy;
28. Therapy-related AML resulting from prior exposure to alkylating agents;
29. Patients who have relapsed < 1 year after receiving an allogeneic transplant for AML. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints:
- To determine the RPTD of AKN-028 for further evaluation in Part 2 (Phase 2) of this study; and
- To determine the overall remissions rate (OR). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Determination of RPTD: The dose at which six patients have been treated and no more than 1 patient developed a DLT will be considered the maximum tolerated dose (MTD), and will be considered the recommended phase two dose (RPTD) to be administered in Part 2 of the study
Overall remission rate is assessed when all patients complete the study. All patients will receive follow-up telephone contacts approximately every 8 weeks until death or until the AKN001 study ends to determine overall survival and progression status.
Remission rate is defined as Complete response + Complete response with incomplete recovery + Partial response.
Response (remission rate) is assessed at the end of each cycle: in Part 1 it is cycle 1 and cycle 2 and in Part 2 it is cycle 1, cycle 2 and cycle 3
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| E.5.2 | Secondary end point(s) |
Exploratory endpoints (in Part 2):
- To explore overall survival of patients with AML treated with AKN-028;
- To determine the clinical activity of AKN-028 based on the standard response criteria by European LeukemiaNet;
o complete remission (CR) rate;
o morphologic leukemia free state (MLFS);
o duration of response assessed by leukemia -free survival (LFS);
- To examine the biologic response to AKN-028 including:
a) Change in peripheral and bone marrow blast counts;
b) Change in neutrophil and platelet counts;
c) Change in bone marrow cellularity;
d) Cytogenetic response; and
e) Improvement in disease-related comorbidities, such as independence from packed RBC transfusions or platelet transfusions as well as infectious complications.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS is assessed when all patients complete the study. All patients will receive follow-up telephone contacts approximately every 8 weeks until death or until the AKN001 study ends to determine overall survival.
The evaluation for clinical activity will be performed after Cycle 1 and every subsequent cycle.
The biological response will be measured as follows:
a) at baseline (for Bone marrow) and Day 21 of each cycle and in case of early termination (both BM and PB) of each cycle
b) at baseline and D1, D3, D8, D15, D21 of each cycle and at FUP 30 days post treatment
c) at baseline and D21 of each cycle
d) at baseline and D21 of each cycle
e) starting from D1 and then at D3 (cycle 1 only), D8, D15, D21 of each cycle and FUP 30 days post treatment
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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 | No |
| 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 | Yes |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Czech Republic |
| Poland |
| Russian Federation |
| Sweden |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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