Leukemia, Myeloid, Acute
Conditions
Keywords
HDM201, midostaurin, cytarabine, daunorubicin, idarubicin, liposomal cytarabine/daunorubicin, acute myeloid leukemia (AML), 1L newly diagnosed AML, relapsed/refractory AML, FLT3-mutation, combination treatment, dose escalation, CR/CRi, minimal residual disease, DDI with CYP3A4 inhibitors, DDI with sensitive CYP3A4 substrate
Brief summary
This is a multi-center open-label Phase I/II study investigating orally administered HDM201 in combination with chemotherapy in two populations: subjects with first line AML or subjects with relapsed/refractory AML. This study is conducted in three parts: dose escalation, dose expansion and DDI study.
Detailed description
This is a Phase 1 / 2 study. No patients were screened / enrolled. There are no data collected. There will be no CSR.
Interventions
DRUGHDM201
2.5 mg and 10mg capsules, given orally
DRUGcytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
DRUGanthracycline
20mg or other strength as locally available given intravenously
DRUGmidostaurin
25mg capsules given orally
DRUGliposomal cytarabine/daunorubicin
100mg/44mg or other strength as locally available given intravenously
DRUGposaconazole
100mg delayed release tablet or other strength as locally available given orally
DRUGmidazolam
2mg/mL oral solution or in other strength as locally available
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3 parts - two different populations Part 1 - escalation - parallel dose escalation in 1L AML subjects and in R/R subjects (up to 8 dose cohorts per arm. Part 2 - expansion - parallel expansion in 3 cohorts of 1L AML, and 1 cohort of R/R AML after recommended dose of expansion was determined. Part 3 - DDI - parallel enrollment or R/R AML subjects into 2 DDI Cohorts (one with CYP3A4 inhibitor, one with CYP3A4 substrate).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All Subjects * Signed informed consent must be obtained prior to participation in the study * Age ≥18 * Diagnosis of AML based on WHO 2016 classification. Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) that is 0 - 2. * Adequate organ functions * Left ventricular ejection fraction \> 45% For 1L AML population: * For Part 1 or Part 2 Expansion Cohorts 1 or 2: subjects with de novo AML suitable for induction treatment with cytarabine and anthracyclines as per investigator judgement * For Part 2 Expansion Cohort 2: documented presence of FLT3 mutation (ITD or TKD ) and suitable for midostaurin treatment as per investigator judgement. * For Part 2 Expansion Cohort 3: Subjects with secondary AML (e.g. AML-MRC , secondary to myelodysplasia/MDS or therapy-related AML). Prior use of hypomethylating agents or other therapies with curative intent for treatment previous hematological malignancies or therapy-related AML is allowed. Subjects suitable for induction treatment with liposomal cytarabine/daunorubicin as per investigator judgement. For R/R AML population: * All Parts: Diagnosis of relapsed or refractory AML and suitable for treatment with IDAC as per investigator judgement. * For Part 3 only: willingness and suitability to participate in DDI Cohort 1 or 2.
Exclusion criteria
* Prior exposure to MDM2 and MDM4 inhibitor (e.g. idasanutlin) * Known symptomatic CNS leukemia not controlled by adequate therapy. * Isolated extramedullary leukemia * Subjects with prior malignancy (some exceptions apply) * QTcF \> 470 ms at screening * Subjects who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment or during the study * Subjects who require use of herbal preparations/medications and dietary supplements within 7 days prior to first dose and during the study * Subjects who require treatment with substrates of CYP3A4/5 with narrow therapeutic index (within 24 hours prior to during and 48 hours after HDM201 administration) * Subjects who require treatment with moderate or strong CYP3A4 inhibitors within 48 hours prior to, during and 48 hours post HDM201 administration. (except for Part 3 DDI Cohort 1 and 2) * Subject is pregnant or breastfeeding * WOCBP unless using highly effective methods of contraception during study treatment and for an appropriate time period after last study treatment * Sexually active males unless they use a condom during intercourse while taking study drug and for an appropriate time period after last study treatment For Part 1 only: \- Subjects with a known favorable risk AML subtype at screening or subjects with FLT3 mutation For Part 3 only: * DDI Cohort 1: use of posaconazole (other than the planned dosing required by the protocol) within 7 days prior to start of the DDI investigation and for the duration of the DDI period * DDI Cohort 2: use of midazolam (other than the planned dosing required by the protocol) within 2 days prior to start of the DDI investigation and for the duration of the DDI period * DDI Cohort 1 and 2: subjects who have received, or are expected to receive moderate or strong inhibitors of CYP3A4 within 7 days prior to start of the DDI investigation, for the duration of the investigation, and 24 hours after last blood sample collection for PK assessment Other protocol-defined inclusion/exclusion may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 - Incidence of dose limiting toxicity (DLT) | first day of study treatment to 3 months after start of study treatment | number of DLTs by dose regimen of first line (1L) acute myeloid leukemia (AML) subjects during induction treatment; number of DLTs by dose regimen of relapsed/refractory (R/R) AML subjects during treatment |
| Part 1 - Time to DLT | first day of study treatment to 3 months after start of study treatment | time from first dose to onset of DLT by dose regimen of 1L AML and R/R AML subjects |
| Part 1 - Incidence and severity of Adverse Events (AEs) | first day of study treatment to 3 months after start of study treatment | number and grade of AEs by dose regimen of 1L AML and R/R AML subjects during DLT observation period |
| Part 2 - Incidence and severity of AEs/serious adverse events (SAEs) | first day of study treatment until 8.5 months after start of study treatment | number and grade of AEs/SAEs by expansion cohort |
| Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR) | first day of study treatment until 4.5 months after start of study treatment | Percentage of participants with CR/CRi with ABCR at the end of induction treatment for Expansion Cohort 1, and at the end of treatment for Expansion Cohort 4 |
| Part 2 - Incidence and severity of abnormal laboratory values | first day of study treatment until 8.5 months after start of study treatment | number and grade of abnormal laboratory results by expansion cohort |
| Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results | first day of study treatment until 8.5 months after start of study treatment | number and severity of abnormal ECG results by expansion cohort |
| Part 2 - Incidence and severity of abnormal vital signs | first day of study treatment until 8.5 months after start of study treatment | number and severity of abnormal vital signs by expansion cohort |
| Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC) | first day of HDM201 dose to 10 days after start of HDM201 | determine HDM201 AUC from time zero to the last measurable concentration sampling time (AUClast) in Cycle 1 |
| Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax) | first day of HDM201 dose to 10 days after start of HDM201 | determine HDM201 Cmax in Cycle 1 |
| Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration | first day of HDM201 dose to 10 days after start of HDM201 | determine HDM201 average plasma concentration in Cycle 1 |
| Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax) | first day of HDM201 dose to 10 days after start of HDM201 | determine HDM201 Tmax in Cycle 1 |
| Part 3 - DDI Cohort 2: midazolam PK AUC | first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201) | determine midazolam AUC last and AUC from time zero to infinity (inf) |
| Part 3 - DDI Cohort 2: midazolam PK Cmax | first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201) | determine midazolam Cmax |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2 - expansion cohort 2: midostaurin PK Cmax | first day of study treatment to 7.5 month after start of study treatment | determine midostaurin Cmax during induction and consolidation treatment |
| Part 2 - expansion cohort 2: midostaurin PK Tmax | first day of study treatment to 7.5 month after start of study treatment | determine midostaurin Tmax during induction and consolidation treatment |
| Part 2 - all Expansion Cohorts: event-free survival | first day of study treatment to 3 years after last patient is enrolled to Part 2 | determine event-free survival by Expansion Cohort |
| Part 1 - incidence of abnormal ECG results | first day of study treatment to 8.5 months after start of study treatment | number of abnormal ECG results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days |
| Part 1 - incidence of abnormal vital signs | first day of study treatment to 8.5 months after start of study treatment | number of abnormal vital signs by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days |
| Part 1 - incidence of abnormal laboratory values | first day of study treatment to 8.5 months after start of study treatment | number of abnormal laboratory results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days |
| Part 1 +2: HDM201 PK AUC | first day of study treatment to 7.5 months after start of study treatment | determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2 |
| Part 1 +2: HDM201 PK Cmax | first day of study treatment to 7.5 months after start of study treatment | determine Cmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2 |
| Part 1 +2: HDM201 PK Tmax | first day of study treatment to 7.5 months after start of study treatment | determine Tmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2 |
| Part 1 - incidence of AEs/SAEs | first day of study treatment to 8.5 months after start of study treatment | number and grade of AEs/SAEs, by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days |
| Part 2 - all Expansion Cohorts: time to platelet recovery | first day of study treatment to 7.5 months after start of study treatment | determine time to platelet recovery by Expansion Cohort for each cycle |
| Part 2 - all Expansion Cohorts: time to neutrophil recovery | first day of study treatment to 7.5 months after start of study treatment | determine time to neutrophil recovery by Expansion Cohort for each cycle |
| Part 2 - all Expansion Cohorts: overall survival | first day of study treatment to 3 years after last patient is enrolled to Part 2 | determine overall survival by Expansion Cohort |
| Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT) | first day of study treatment to 3 years after last patient was enrolled to Part 2 | percentage of subjects receiving HSCT after study treatment by Expansion Cohort. |
| Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS) | first day of study treatment to 3 years after last patient enrolled to Part 2 | determine DFS by Expansion Cohort |
| Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR) | first day of study treatment to 3 years after last patient enrolled to Part 2 | determine CIR by Expansion Cohort |
| Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR | first day of study treatment to 7.5 months after start of study treatment | proportion of subjects achieving CR or CRi with ABCR by Expansion Cohort |
| Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity | first day of study treatment to 7.5 months after start of study treatment | proportion of subjects achieving MRD negativity by Expansion Cohort |
| Part 2 - expansion cohort 2: midostaurin PK AUC | first day of study treatment to 7.5 month after start of study treatment | determine midostaurin AUC |
Outcome results
None listed