| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or refractory Acute Myeloid Leukemia |
| Leucemia mieloide acuta recidivante o refrattaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed and/or refractory leukemia |
| Leucemia mieloide acuta recidivante o refrattaria |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060558 |
| E.1.2 | Term | Acute myeloid leukemia recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Part 1a: Dose-Escalation
- To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of KO-539 in patients with relapsed or refractory acute myeloid leukemia (AML).
Part 1b: Dose-Validation/ Cohort Expansion
- Determine the safety, tolerability and minimal biologically effective dose of KO-539 in dosing cohorts which have demonstrated early biological activity and have been determined to be safe as part of the dose-escalation phase.
|
Parte 1a: Incremento della dose
- Determinare la dose massima tollerata (MTD) e/o la dose raccomandata per la Fase 2 (RP2D) di KO-539 in pazienti affetti da leucemia mieloide acuta (LMA) recidivante o refrattaria.
Parte 1b: Validazione della dose/Espansione della coorte
- Determinare la sicurezza, la tollerabilità e la dose minima biologicamente efficace di KO-539 nelle coorti di dosaggio che hanno dimostrato un’attività biologica precoce e che sono state ritenute sicure nell’ambito della fase di incremento della dose. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1a: Dose-Escalation
- To investigate the safety and tolerability of KO-539
- To characterize the PK of KO-539 after single po dose administration and after multiple po dose administrations.
- Explore early evidence of anti-leukemic activity (ALA):
• Composite of CR plus CR with partial hematologic recovery (CRh)
• CR with and without minimal residual disease (MRD)
• Duration of remission (DOR)
Part 1b: Dose-Validation/ Cohort Expansion
- Explore early evidence of ALA:
•Composite of CR plus CRh
•CR with and without MRD
•DOR
•Transfusion Independence (TI)
•Relapse-free survival (RFS)
•OS |
Parte 1a: Incremento della dose
- Investigare la sicurezza e la tollerabilità di KO-539
- Caratterizzare la farmacocinetica (PK) di KO-539 dopo la somministrazione di una singola dose po e dopo somministrazioni di dosi multiple po.
- Esplorare l’evidenza precoce dell’attività antileucemica (ALA):
• Composito di remissione completa (CR) più CR con recupero ematologico parziale (CRh)
• CR con e senza malattia minima residua (MRD)
• Durata della remissione (DOR)
Parte 1b: Validazione della dose/Espansione della coorte
- Esplorare l’evidenza precoce dell’ALA:
• Composito di CR più CRh
• CR con e senza MRD
• DOR
• Indipendenza trasfusionale (TI)
• Sopravvivenza libera da recidiva (RFS)
• Sopravvivenza complessiva (OS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For all parts:
1. Refractory or relapsed AML defined as the reappearance of >=5% blasts in the bone marrow and who have also failed or are not eligible for any approved standard of care therapies, including hematopoietic stem cell transplantation (HSCT).
2. >=18 years of age.
3. Read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures including serial bone marrow and peripheral blood sampling.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
5. Adequate organ function including:
• creatinine <=2.0 × upper limit of normal (ULN) OR creatinine clearance >=40 mL/min using the Cockcroft-Gault equation;
• serum bilirubin <=1.5 × ULN (unless known Gilbert’s syndrome or secondary to leukemic disease); aspartate aminotransferase and alanine aminotransferase <=2.0 × ULN.
6. Peripheral white blood cell (WBC) counts <=30,000/µL. Patients are allowed to receive hydroxyurea to control and maintain WBC count prior to enrollment and can continue on hydroxyurea through Cycle 1 Day 28 or until first disease assessment. After which, approval by Kura Medical Monitor is required.
7. Women of childbearing potential (WOCBP) must be willing to use a highly effective method of contraception throughout the study and study follow-up or for at least 90 days after the last dose of study treatment. NOTE: A woman is considered to be of non-childbearing potential if she meets one of the following criteria: a) post-menopausal with at least 12 months of spontaneous amenorrhea; b) has had a bilateral oophorectomy; or c) has had a hysterectomy.
8. Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and study follow-up or for at least 90 days after the last dose of study treatment. All men with female partners of childbearing potential will be instructed to contact the Investigator immediately if their partner becomes pregnant at any time during study participation. All men must agree not to donate semen throughout the study and for 90 days after the last dose of study treatment.
In Part 1b Dose-Validation/ Cohort Expansion, patients must meet ALL of the above inclusion criteria as well as:
1. Adult patients that have documented specific genetic subtypes determined by local institutional genomic testing and defined as either lysine[K]-specific methyltransferase 2-rearranged (KMT2A-r) or nucleophosmin 1-mutant (NPM1-m). |
Per tutte le parti:
1. LMA refrattaria o recidivante, definita come ricomparsa di >=5% di blasti nel midollo osseo, e che non hanno risposto o non sono idonei ad alcuna terapia standard approvata, incluso il trapianto di cellule staminali ematopoietiche (HSCT).
2. Età >=18 anni.
3. Aver letto, compreso e fornito il consenso informato scritto e, se applicabile, l’autorizzazione della Legge sulla portabilità e responsabilità dell’assicurazione sanitaria (HIPAA) dopo aver ricevuto spiegazioni esaustive sulla natura dello studio, ed essere disposti a rispettare tutti i requisiti e le procedure dello studio, compresi i prelievi seriali di midollo osseo e sangue periferico.
4. Stato di validità secondo il Gruppo cooperativo orientale di oncologia (ECOG) da 0 a 2.
5. Adeguata funzionalità degli organi, tra cui:
• creatinina <=2,0 × limite superiore della norma (ULN) OPPURE clearance della creatinina >=40 ml/min utilizzando l’equazione di Cockcroft-Gault;
• bilirubina sierica <=1,5 × ULN (salvo sindrome di Gilbert nota o secondaria alla malattia leucemica); aspartato aminotransferasi e alanina aminotransferasi <=2,0 × ULN.
6. Conta dei globuli bianchi periferici (WBC) <=30.000/µl. I pazienti potranno ricevere idrossiurea per controllare e mantenere la conta dei WBC prima dell’arruolamento e potranno continuare con l’idrossiurea fino al Giorno 28 del Ciclo 1 o fino alla prima valutazione della malattia. Dopo di ciò occorrerà l’approvazione del responsabile del monitoraggio medico di Kura.
7. Le donne in età fertile (WOCBP) dovranno essere disposte a utilizzare un metodo contraccettivo altamente efficace per tutta la durata dello studio e del follow-up dello studio o per almeno 90 giorni dopo l’ultima dose del trattamento dello studio. NOTA: Una donna è considerata non in età fertile se soddisfa uno dei seguenti criteri: a) è in post-menopausa con almeno 12 mesi di amenorrea spontanea; b) ha subito un’ovariectomia bilaterale; o c) è stata sottoposta a isterectomia.
8. I pazienti di sesso maschile con compagne di sesso femminile in età fertile dovranno accettare di utilizzare un metodo contraccettivo altamente efficace per tutta la durata dello studio e del follow-up dello studio per almeno 90 giorni dopo l’ultima dose del trattamento dello studio. Tutti i pazienti di sesso maschile con compagne di sesso femminile in età fertile saranno istruiti a contattare immediatamente lo Sperimentatore se la loro compagna rimane incinta in qualsiasi momento durante la partecipazione allo studio. Tutti i pazienti di sesso maschile dovranno acconsentire a non donare il liquido seminale per tutta la durata dello studio e per 90 giorni dopo l’ultima dose del trattamento dello studio.
Nella Parte 1b, Validazione della dose/Espansione della coorte, i pazienti dovranno soddisfare TUTTI i criteri di inclusione di cui sopra, nonché:
1. Pazienti adulti che presentano sottotipi genetici specifici documentati, determinati mediante test genomici istituzionali locali e definiti come metiltransferasi 2-riarrangiata specifica per la lisina[K] (KMT2A-r) o nucleofosmina 1-mutante (NPM1-m). |
|
| E.4 | Principal exclusion criteria |
For Part 1a – Dose-Escalation and Part 1b – Dose-Validation/ Cohort Expansion:
1. Patient has a diagnosis of acute promyelocytic leukemia.
2. Patient has a diagnosis of chronic myelogenous leukemia in blast crisis.
3. Donor lymphocyte infusion < 30 days prior to study entry.
4. Clinically active central nervous system (CNS) leukemia. A patient is considered eligible if CNS leukemia is controlled and patient is receiving intrathecal therapy at study entry. Patients should continue to receive intrathecal therapy (or cranial radiation) as clinically indicated.
5. Patients who have undergone HSCT and have not had adequate hematologic recovery (i.e. absolute neutrophil count [ANC] >1000 and platelet count > 100,000).
6. Patients on immunosuppressive therapy post HSCT at the time of screening (must be off all immunosuppression therapy for at least 2 weeks). The use of topical steroids for cutaneous graft-versus-host disease (GVHD) is allowed and stable steroid doses less than or equal to 20 mg of prednisone daily is permitted with Kura Medical Monitor approval.
7. Grade > 2 active GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.
8. Patient has received chemotherapy, immunotherapy, radiotherapy or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) <=14 days prior to the first dose of KO-539.
9. Patients who have not recovered to NCI CTCAE <= v5.0 Grade 2 from all acute toxicities or deemed back to a stable baseline.
10. Patient requires treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450 (CYP)3A4 with the exception of antibiotics, antifungals, and antivirals that are used as standard of care to prevent or treat infections. Other such drugs that are considered absolutely essential for the care of the patient should be discussed on a case by case basis with the Kura Medical Monitor.
11. Patient has a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection.
12. Patient has a pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g., cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML).
13. Patient has an active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.
14. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, history of cerebrovascular accident including transient ischemic attack within the past 6 months, congestive heart failure (New York Heart Association [NYHA] Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the first dose of study treatment.
15. Mean corrected QT interval by Fredericia’s formula (QTcF) >480 ms on triplicate electrocardiograms (ECGs) performed within 5 minutes of each other. Please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or increase risk of torsades de pointes.
16. Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and patients should be recovered.
17. Underlying medical condition that, in the Principal Investigator’s opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events (AEs).
18. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
19. Known alcohol or drug abuse or dependence. |
Parte 1a - Incremento della dose e Parte 1b - Validazione della dose/Espansione della coorte:
1. Il paziente ha una diagnosi di leucemia promielocitica acuta.
2. Il paziente ha una diagnosi di leucemia mieloide cronica in crisi blastica.
3. Infusione linfocitaria del donatore <30 giorni prima dell’ingresso nello studio.
4. Leucemia del sistema nervoso centrale (SNC) clinicamente attiva. Un paziente sarà considerato idoneo se la leucemia del SNC è controllata e il paziente sta ricevendo una terapia intratecale al momento dell’ingresso nello studio. I pazienti dovranno continuare a ricevere la terapia intratecale (o irradiazione cranica) come clinicamente indicato.
5. Pazienti che si sono sottoposti a HSCT e non hanno avuto un adeguato recupero ematologico (ovvero, conta assoluta dei neutrofili [ANC] >1000 e conta piastrinica >100.000).
6. Pazienti in terapia immunosoppressiva post HSCT al momento dello screening (devono aver sospeso tutta la terapia immunosoppressiva da almeno 2 settimane). Sarà consentito l’uso di steroidi topici per la malattia del trapianto contro l’ospite (GVHD) cutanea, mentre dosi stabili di steroidi, inferiori o uguali a 20 mg di prednisone al giorno, saranno consentite con l’approvazione del responsabile del monitoraggio medico di Kura.
7. GVHD attiva di grado >2, GVHD cronica limitata di entità moderata o grave o GVHD cronica estesa di qualsiasi gravità.
8. Il paziente ha ricevuto chemioterapia, immunoterapia, radioterapia o qualsiasi terapia ancillare considerata sperimentale (ovvero utilizzata per indicazioni non approvate e nel contesto di un’indagine di ricerca) <=14 giorni prima della prima dose di KO-539.
9. Pazienti che non si sono ripresi da tutte le tossicità acute fino al Grado 2 dei criteri NCI CTCAE <= v5.0 o che non si ritiene siano tornati a un basale stabile.
10. Il paziente richiede un trattamento con farmaci concomitanti che sono forti inibitori o induttori del citocromo P450 (CYP)3A4, ad eccezione di antibiotici, antimicotici e antivirali utilizzati come standard di cura per prevenire o trattare le infezioni. Altri farmaci considerati assolutamente essenziali per la cura del paziente dovranno essere discussi caso per caso con il responsabile del monitoraggio medico di Kura.
11. Il paziente presenta una carica virale nota rilevabile per il virus dell’immunodeficienza umana o dell’epatite C, o evidenza di un antigene di superficie dell’epatite B, tutti indicativi di infezione attiva.
12. Il paziente presenta un disturbo preesistente che predispone il paziente a un’infezione seria o potenzialmente letale (ad es. fibrosi cistica, immunodeficienza congenita o acquisita, disturbo emorragico o citopenie non correlati alla LMA).
13. Il paziente presenta un’infezione micotica, batterica, virale o di altro tipo acuta o cronica attiva, non controllata.
14. Malattia cardiovascolare significativa, tra cui angina pectoris instabile, ipertensione o aritmia non controllata, anamnesi di ictus cerebrovascolare, tra cui attacco ischemico transitorio negli ultimi 6 mesi, scompenso cardiaco congestizio (di Classe III o IV secondo la New York Heart Association [NYHA]) correlata a cardiopatia primaria, cardiopatia valvolare ischemica o grave o infarto miocardico nei 6 mesi precedenti la prima dose del trattamento dello studio.
15. Intervallo QT medio corretto in base alla formula di Fredericia (QTcF) >480 ms su elettrocardiogramma (ECG) da eseguire in triplicato a distanza di 5 minuti l’uno dall’altro. Per un elenco dei farmaci che prolungano il QT e/o aumentano il rischio di torsade de pointes.......... |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Maximum Tolerated Dose (MTD)
• Recommended Phase 2 dose (RP2D) |
• Maximum Tolerated Dose (MTD)
• Recommended Phase 2 dose (RP2D) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At any time during the clinical trial. Disease assessment will be done when there is clinical evidence of response. |
| At any time during the clinical trial. Disease assessment will be done when there is clinical evidence of response. |
|
| E.5.2 | Secondary end point(s) |
Safety
• Incidence of AEs
• Deaths on study
• Discontinuations of study treatment due to AEs
• Clinically significant changes in hematology, serum chemistry, urinalysis, and other laboratory parameters
• Clinically significant changes in vital sign parameters
• Clinically significant changes in ECG parameters
• Clinically meaningful declines in ECOG status
Anti-leukemic Activity (ALA)
• Composite of complete CR plus CRh
• CR with and without MRD
• DOR
• TI
• RFS
• OS
Pharmacokinetics
• Plasma concentrations of KO-539
• Metabolite(s) of KO-539
• Concentration of KO-539 in bone marrow. |
Safety
• Incidence of AEs
• Deaths on study
• Discontinuations of study treatment due to AEs
• Clinically significant changes in hematology, serum chemistry, urinalysis, and other laboratory parameters
• Clinically significant changes in vital sign parameters
• Clinically significant changes in ECG parameters
• Clinically meaningful declines in ECOG status
Anti-leukemic Activity (ALA)
• Composite of complete CR plus CRh
• CR with and without MRD
• DOR
• TI
• RFS
• OS
Pharmacokinetics
• Plasma concentrations of KO-539
• Metabolite(s) of KO-539
• Concentration of KO-539 in bone marrow. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At any time during the clinical trial. Disease assessment will be done when there is clinical evidence of response. |
| At any time during the clinical trial. Disease assessment will be done when there is clinical evidence of response. |
|
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 | Information not present in EudraCT |
| 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 |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
|
| 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
|
| Last visit of the last subject (LVLS) |
| Last visit of the last subject (LVLS) |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 |
Print
