HDM201 Added to CT in R/R or Newly Diagnosed AML

Novartis Pharmaceuticals

Overview

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.

This is a Phase 1 / 2 study. No patients were screened / enrolled. There are no data collected. There will be no CSR.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Conditions

Leukemia, Myeloid, Acute

Interventions

HDM201DRUG

2.5 mg and 10mg capsules, given orally

cytarabineDRUG

20mg or 1000 mg or other strengths as locally available given intravenously

anthracyclineDRUG

20mg or other strength as locally available given intravenously

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Part 1 - Incidence of dose limiting toxicity (DLT)

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

Time frame: first day of study treatment to 3 months after start of study treatment

Part 1 - Time to DLT

time from first dose to onset of DLT by dose regimen of 1L AML and R/R AML subjects

Time frame: first day of study treatment to 3 months after start of study treatment

Part 1 - Incidence and severity of Adverse Events (AEs)

number and grade of AEs by dose regimen of 1L AML and R/R AML subjects during DLT observation period

Time frame: first day of study treatment to 3 months after start of study treatment

Part 2 - Incidence and severity of AEs/serious adverse events (SAEs)

number and grade of AEs/SAEs by expansion cohort

Time frame: first day of study treatment until 8.5 months after start of study treatment

Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR)

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

Time frame: first day of study treatment until 4.5 months after start of study treatment

Part 2 - Incidence and severity of abnormal laboratory values

number and grade of abnormal laboratory results by expansion cohort

Time frame: first day of study treatment until 8.5 months after start of study treatment

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1 +2: HDM201 PK AUC

determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 1 +2: HDM201 PK Cmax

determine Cmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 1 +2: HDM201 PK Tmax

determine Tmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 1 - incidence of AEs/SAEs

number and grade of AEs/SAEs, by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

Time frame: first day of study treatment to 8.5 months after start of study treatment

Part 2 - all Expansion Cohorts: time to platelet recovery

determine time to platelet recovery by Expansion Cohort for each cycle

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 2 - all Expansion Cohorts: time to neutrophil recovery

determine time to neutrophil recovery by Expansion Cohort for each cycle

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 2 - all Expansion Cohorts: overall survival

determine overall survival by Expansion Cohort

Time frame: first day of study treatment to 3 years after last patient is enrolled to Part 2

Part 2 - all Expansion Cohorts: event-free survival

determine event-free survival by Expansion Cohort

Time frame: first day of study treatment to 3 years after last patient is enrolled to Part 2

Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT)

percentage of subjects receiving HSCT after study treatment by Expansion Cohort.

Time frame: first day of study treatment to 3 years after last patient was enrolled to Part 2

Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS)

determine DFS by Expansion Cohort

Time frame: first day of study treatment to 3 years after last patient enrolled to Part 2

Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR)

determine CIR by Expansion Cohort

Time frame: first day of study treatment to 3 years after last patient enrolled to Part 2

Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR

proportion of subjects achieving CR or CRi with ABCR by Expansion Cohort

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity

proportion of subjects achieving MRD negativity by Expansion Cohort

Time frame: first day of study treatment to 7.5 months after start of study treatment

Part 2 - expansion cohort 2: midostaurin PK AUC

determine midostaurin AUC

Time frame: first day of study treatment to 7.5 month after start of study treatment

Part 2 - expansion cohort 2: midostaurin PK Cmax

determine midostaurin Cmax during induction and consolidation treatment

Time frame: first day of study treatment to 7.5 month after start of study treatment

Part 2 - expansion cohort 2: midostaurin PK Tmax

determine midostaurin Tmax during induction and consolidation treatment

Time frame: first day of study treatment to 7.5 month after start of study treatment

Part 1 - incidence of abnormal laboratory values

number of abnormal laboratory results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

Time frame: first day of study treatment to 8.5 months after start of study treatment

Part 1 - incidence of abnormal ECG results

number of abnormal ECG results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

Time frame: first day of study treatment to 8.5 months after start of study treatment

Part 1 - incidence of abnormal vital signs

number of abnormal vital signs by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

Time frame: first day of study treatment to 8.5 months after start of study treatment