Relapsed refractory (R/R) or newly diagnosed acute myeloid leukemia (AML)
Conditions
Interventions
Product Code: HDM201
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: not available yet
Current Sponsor code: HDM201
Other descriptive name: HDM201
Concentration unit: mg milligram(s)
Concentra
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All subjects 1. Signed informed consent must be obtained prior to participation in the study. 2. Age = 18 years at the date of signing the informed consent form (ICF). 3. Diagnosis of AML based on WHO 2016 classification (Arber et al 2016). Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible. 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) that is 0 to 2 5. Adequate organ functions: • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 × upper limit of normal (ULN) • Total bilirubin (TBL) = 1.5 × ULN (except in the setting of isolated Gilbert syndrome) • Glomerular Filtration Rate (estimation based on Cockcroft-Gault formula) = 30 mL/min 6. Left ventricular ejection fraction (LVEF) > 45% R/R AML subjects eligible for inclusion in this study must additionally meet the following criteria: 7. Diagnosis of relapsed or refractory AML 8. Suitable for treatment with intermediate dose cytarabine (IDAC) as per investigator judgement 9. For Part 3 only: willing and suitable to participate in DDI Cohort 1 or 2 1L AML subjects eligible for inclusion in this study must additionally meet the following criteria, as applicable to the part/cohort they are to be enrolled in: For Part 1 or Part 2 Expansion Cohort 1 or Part 2 Expansion Cohort 2 only: 10. Subjects with de novo AML 11. Suitable for induction treatment with cytarabine and anthracyclines as per investigator judgement For Part 2 Expansion Cohort 2 only: 12. Documented presence of FLT3 mutation (ITD or TKD) 13. Suitable for midostaurin treatment as per investigator judgement For Part 3 Expansion Cohort 3 only: 14. Subjects with secondary AML (e.g. AML with Myelodysplasia-Related Changes/AML-MRC, AML secondary to myelodysplasia/MDS or therapy-related AML). Prior use of hypomethylating agents or other therapies with curative intent for treating previous hematological malignancies or therapy-related AML is allowed. 15. Suitable for induction treatment with liposomal cytarabine/daunorubicin as per investigator judgement Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 135 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 45
Exclusion criteria
Exclusion criteria: All subjects 1. Prior exposure to MDM2 and MDM4 inhibitor (eg, idasanutlin) 2. Known CNS leukemia with signs or symptoms that are not controlled by adequate therapy. 3. Isolated extramedullary leukemia 4. For Part 1 only: subjects with a known favorable-risk AML subtype at screening 5. For Part 1 only: subjects with documented FLT3 mutation. 6. Subjects with prior malignancy, except for: a) Adequately treated solid tumor for which the subject has been disease free for at least 2 years and if no anticancer therapy is ongoing or required during the course of the study; b) Subjects with history of hematological malignancies leading to secondary AML (eg, myelodysplasia/ myelodysplastic syndrome (MDS)) and subjects with therapy-related AML will not be excluded in dose Expansion Cohort 3. 7. Any concurrent severe and/or uncontrolled medical condition eg, a) cardiovascular disease including congestive heart failure, or b) active uncontrolled infection requiring parenteral antibacterial, antiviral or antifungal therapy compromised by hemodynamic instability 8. QTcF > 470 ms at screening 9. Any other known disease that could compromise participation in the study including gastrointestinal (GI) disorders impacting absorption of HDM201, evidence of major active bleeding or history of bleeding diathesis or major coagulopathy not related to AML 10. Known confirmed diagnosis of human immunodeficiency virus (HIV) infection 11. Evidence of active hepatitis B (HBV) or hepatitis C (HCV) viral infection (hepatitis B surface antigen (HBsAg) in the absence of hepatitis B surface antibody (HBsAb) OR HCV Ab (antibody) positive with HCV RNA (ribonucleic acid) positive) 12. Subjects who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 inducers during the entire study 13. Subjects who require the use of herbal preparations/medications and dietary supplements (except for vitamins) within 7 days prior to first dose of study treatment or are expected to use such products during the entire study 14. Subjects who require treatment with substrates of CYP3A4/5 with a narrow therapeutic index (within 24 hours prior to, during and 48 hours after HDM201 administration). 15. Subjects taking medications with a known risk of prolonging the QT interval or inducing Torsade de pointes, if such medication cannot be discontinued or replaced safely with an alternative medication prior to starting first dose of HDM201 16. Subjects who require treatment with moderate or strong CYP3A4 inhibitors within 48 hours prior to, during and 48 hours post HDM201 administration. Of note, this is not applicable for Part 3 Cycle 1 17. Subject is pregnant or breastfeeding 18. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 weeks after HDM201 discontinuation or for 4 months after midostaurin discontinuation (for 1L AML Expansion Cohort 2) or for 6 months after liposomal cytarabine/daunorubicin discontinuation (for 1L AML Expansion Cohort 3) Highly effective contraception methods are described in the protocol. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate history of vas
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of Part 1 of this study is to determine RDE of HDM201 combined with CT in subjects with 1L and in subjects with R/R AML. The primary objective of Part 2 of this study is to assess whether RDE of HDM201 combined with CT in 1L AML subjects enrolled to Expansion Cohort 1 (without documented FLT3 mutation) and in subjects with R/R AML enrolled to Expansion Cohort 4, respectively is the RP3D. For 1L AML subjects enrolled to Expansion Cohorts 2 and 3, the primary objective will be the safety and tolerability of HDM201 in combination with CT. The primary objective of Part 3 of this study is to evaluate in DDI Cohort 1, the adjusted dose of HDM201 that may be needed when a strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor (posaconazole) is used in subjects treated with HDM201, and to evaluate in DDI Cohort 2 the effect of multiple doses of HDM201 on the PK of a single oral dose of a sensitive CYP3A4 substrate (midazolam). ;Secondary Objective: The secondary objectives of Part 1 of this study are to assess PK, as well as safety and tolerability of HDM201 in combination with CT in both study populations (1L AML without documented FLT3 mutation and R/R AML subjects irrespective of FLT 3 mutation status). The secondary objectives of Part 2 of this study are to assess PK of HDM201 at RDE, efficacy and blood count recovery of treatment with HDM201 in combination with CT in Expansion Cohorts 1, 3, and 4 and in combination with CT and midostaurin in Expansion Cohort 2. In Expansion Cohort 2 also the PK of midostaurin in combination with HDM201 at RDE and CT will be assessed. Minimal/measurable residual disease (MRD) negativity will be assessed in Expansion Cohorts 1 and 2. ;Primary end point(s): Part 1: 1L AML subjects • Incidence of DLT and time to DLT in subjects receiving induction therapy • Incidence and severity of AEs in 1L AML subjects R/R AML subjects • Incidence of DLT and time to DLT • Incidence an | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part 1: 1L AML and R/R AML subjects • PK parameters of HDM201 (e.g., AUC, Cmax, Tmax) • Incidence of AEs, SAEs and abnormal laboratory values, ECG and vital signs Part 2: Expansion Cohort 1 • OS, DFS, CIR , EFS • Proportion of subjects receiving HSCT • Proportion of subjects with MRD negativity Expansion Cohort 2 • OS, DFS, CIR , EFS, proportion of subjects with CR/CRi with ABCR • Proportion of subjects receiving HSCT • Proportion of subjects with MRD negativity • PK parameters of midostaurin (e.g., AUC, Cmax, Tmax) Expansion Cohort 3 • OS, DFS, CIR , EFS, proportion of CR/CRi with ABCR • Proportion of subjects receiving HSCT Expansion Cohort 4 • OS, EFS • Proportion of subjects receiving HSCT All Expansion Cohorts • PK parameters of HDM201 (e.g., AUC, Cmax, Tmax) • Time to platelet recovery, time to neutrophil recovery Part 3: DDI Cohort 1 • Overall safety information in subjects in DDI Cohort 1 DDI Cohort 2 • Overall safety information in subjects in DDI Cohort 2 ;Timepoint(s) of evaluation of this end point: Part 1: 1L AML and R/R AML subjects - D1 of ST to 7.5 m after start of ST - D1 of ST to 8.5 m after start of ST Part 2: Expansion Cohort 1 - D1 of ST to 3 y after last patients is enrolled in Part 2 - D1 of ST to 3 y after last patients is enrolled in Part 2 - D1 of ST to 7.5 m after start of ST | — |
Countries
Australia, Belgium, Canada, Finland, France, Germany, Hong Kong, Israel, Italy, Japan, Lebanon, Singapore, Spain, United Kingdom, United States
Contacts
Public ContactMedizinischer Infoservice
Novartis Pharma GmbH
Outcome results
None listed