Clinical trial NCT03760445: HDM201 Added to CT in R/R or Newly Diagnosed AML
Official title: A Phase I/II Multi-center Study of HDM201 Added to Chemotherapy in Adult Subjects With Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-11-30
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part 1 - Incidence of dose limiting toxicity (DLT)
timeFrame: first day of study treatment to 3 months after start of study treatment
measure: Part 1 - Time to DLT
timeFrame: first day of study treatment to 3 months after start of study treatment
measure: Part 1 - Incidence and severity of Adverse Events (AEs)
timeFrame: first day of study treatment to 3 months after start of study treatment
measure: Part 2 - Incidence and severity of AEs/serious adverse events (SAEs)
timeFrame: first day of study treatment until 8.5 months after start of study treatment
measure: Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR)
timeFrame: first day of study treatment until 4.5 months after start of study treatment
measure: Part 2 - Incidence and severity of abnormal laboratory values
timeFrame: first day of study treatment until 8.5 months after start of study treatment
measure: Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results
timeFrame: first day of study treatment until 8.5 months after start of study treatment
measure: Part 2 - Incidence and severity of abnormal vital signs
timeFrame: first day of study treatment until 8.5 months after start of study treatment
measure: Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC)
timeFrame: first day of HDM201 dose to 10 days after start of HDM201
measure: Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax)
timeFrame: first day of HDM201 dose to 10 days after start of HDM201
measure: Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration
timeFrame: first day of HDM201 dose to 10 days after start of HDM201
measure: Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax)
timeFrame: first day of HDM201 dose to 10 days after start of HDM201
measure: Part 3 - DDI Cohort 2: midazolam PK AUC
timeFrame: first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)
measure: Part 3 - DDI Cohort 2: midazolam PK Cmax
timeFrame: first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)
Secondary outcomes:
measure: Part 1 +2: HDM201 PK AUC
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 1 +2: HDM201 PK Cmax
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 1 +2: HDM201 PK Tmax
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 1 - incidence of AEs/SAEs
timeFrame: first day of study treatment to 8.5 months after start of study treatment
measure: Part 2 - all Expansion Cohorts: time to platelet recovery
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 2 - all Expansion Cohorts: time to neutrophil recovery
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 2 - all Expansion Cohorts: overall survival
timeFrame: first day of study treatment to 3 years after last patient is enrolled to Part 2
measure: Part 2 - all Expansion Cohorts: event-free survival
timeFrame: first day of study treatment to 3 years after last patient is enrolled to Part 2
measure: Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT)
timeFrame: first day of study treatment to 3 years after last patient was enrolled to Part 2
measure: Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS)
timeFrame: first day of study treatment to 3 years after last patient enrolled to Part 2
measure: Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR)
timeFrame: first day of study treatment to 3 years after last patient enrolled to Part 2
measure: Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity
timeFrame: first day of study treatment to 7.5 months after start of study treatment
measure: Part 2 - expansion cohort 2: midostaurin PK AUC
timeFrame: first day of study treatment to 7.5 month after start of study treatment
measure: Part 2 - expansion cohort 2: midostaurin PK Cmax
timeFrame: first day of study treatment to 7.5 month after start of study treatment
measure: Part 2 - expansion cohort 2: midostaurin PK Tmax
timeFrame: first day of study treatment to 7.5 month after start of study treatment
measure: Part 1 - incidence of abnormal laboratory values
timeFrame: first day of study treatment to 8.5 months after start of study treatment
measure: Part 1 - incidence of abnormal ECG results
timeFrame: first day of study treatment to 8.5 months after start of study treatment
measure: Part 1 - incidence of abnormal vital signs
timeFrame: first day of study treatment to 8.5 months after start of study treatment
Other outcomes:
Locations:
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: