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

NCT03760445 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: CHDM201A21012018-003107-19
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

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

Outcome Measures

Primary Outcomes (14)

• 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

  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

  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

  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

  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

  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

  first day of study treatment until 8.5 months after start of study treatment

• Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results

  number and severity of abnormal ECG results by expansion cohort

  first day of study treatment until 8.5 months after start of study treatment

• Part 2 - Incidence and severity of abnormal vital signs

  number and severity of abnormal vital signs by expansion cohort

  first day of study treatment until 8.5 months after start of study treatment

• Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC)

  determine HDM201 AUC from time zero to the last measurable concentration sampling time (AUClast) in Cycle 1

  first day of HDM201 dose to 10 days after start of HDM201

• Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax)

  determine HDM201 Cmax in Cycle 1

  first day of HDM201 dose to 10 days after start of HDM201

• Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration

  determine HDM201 average plasma concentration in Cycle 1

  first day of HDM201 dose to 10 days after start of HDM201

• Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax)

  determine HDM201 Tmax in Cycle 1

  first day of HDM201 dose to 10 days after start of HDM201

• Part 3 - DDI Cohort 2: midazolam PK AUC

  determine midazolam AUC last and AUC from time zero to infinity (inf)

  first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)

• Part 3 - DDI Cohort 2: midazolam PK Cmax

  determine midazolam Cmax

  first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)

Secondary Outcomes (19)

• Part 1 +2: HDM201 PK AUC

  first day of study treatment to 7.5 months after start of study treatment

• Part 1 +2: HDM201 PK Cmax

  first day of study treatment to 7.5 months after start of study treatment

• Part 1 +2: HDM201 PK Tmax

  first day of study treatment to 7.5 months after start of study treatment

• Part 1 - incidence of AEs/SAEs

  first day of study treatment to 8.5 months after start of study treatment

• Part 2 - all Expansion Cohorts: time to platelet recovery

  first day of study treatment to 7.5 months after start of study treatment

Study Arms (8)

Part 1 - first line (1L) AML

EXPERIMENTAL

1L acute myeloid leukemia (AML) subjects receiving HDM201 in various doses/schedules in combination with cytarabine/anthracyclines

Drug: HDM201; Drug: cytarabine; Drug: anthracycline

Part 1 - relapsed/refractory (R/R) AML

EXPERIMENTAL

R/R AML subjects receiving HDM201 in various doses/schedules in combination with cytarabine

Drug: HDM201; Drug: cytarabine

Part 2 - Expansion Cohort 1

EXPERIMENTAL

1L de novo AML subjects without documented FLT3 mutation receiving HDM201 at the recommended dose of expansion (RDE) in combination with cytarabine/anthracyclines

Drug: HDM201; Drug: cytarabine; Drug: anthracycline

Part 2 - Expansion Cohort 2

EXPERIMENTAL

1L de novo AML subjects with documented FLT3 mutation status receiving HDM201 at RDE in combination with cytarabine/anthracyclines and midostaurin

Drug: HDM201; Drug: cytarabine; Drug: anthracycline; Drug: midostaurin

Part 2 - Expansion Cohort 3

EXPERIMENTAL

1L secondary AML subjects receiving HDM201 at RDE in combination with liposomal cytarabine/daunorubicin

Drug: HDM201; Drug: cytarabine; Drug: liposomal cytarabine/daunorubicin

Part 2 - Expansion Cohort 4

EXPERIMENTAL

R/R AML subjects receiving HDM201 at RDE in combination with cytarabine

Drug: HDM201; Drug: cytarabine

Part 3 - DDI Cohort 1

EXPERIMENTAL

R/R AML subjects receiving HDM201 at adjusted recommended Phase 3 dose (RP3D) determined in Part 2 in combination with cytarabine and posaconazole added in Cycle 1

Drug: HDM201; Drug: cytarabine; Drug: posaconazole

Part 3 - DDI Cohort 2

EXPERIMENTAL

R/R AML subjects receiving HDM201 at RP3D in combination with cytarabine and midazolam

Drug: HDM201; Drug: cytarabine; Drug: midazolam

Interventions

HDM201 DRUG

2.5 mg and 10mg capsules, given orally

Also known as: none available

Part 1 - first line (1L) AML; Part 1 - relapsed/refractory (R/R) AML; Part 2 - Expansion Cohort 1; Part 2 - Expansion Cohort 2; Part 2 - Expansion Cohort 3; Part 2 - Expansion Cohort 4; Part 3 - DDI Cohort 1; Part 3 - DDI Cohort 2

cytarabine DRUG

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

Also known as: Ara-C, Cytosar

Part 1 - first line (1L) AML; Part 1 - relapsed/refractory (R/R) AML; Part 2 - Expansion Cohort 1; Part 2 - Expansion Cohort 2; Part 2 - Expansion Cohort 3; Part 2 - Expansion Cohort 4; Part 3 - DDI Cohort 1; Part 3 - DDI Cohort 2

anthracycline DRUG

20mg or other strength as locally available given intravenously

Also known as: daunorubicin or idarubicin, Rubidomycin or Idamycin

Part 1 - first line (1L) AML; Part 2 - Expansion Cohort 1; Part 2 - Expansion Cohort 2

midostaurin DRUG

25mg capsules given orally

Also known as: PKC412, Rydapt

Part 2 - Expansion Cohort 2

liposomal cytarabine/daunorubicin DRUG

100mg/44mg or other strength as locally available given intravenously

Also known as: Vyxeos

Part 2 - Expansion Cohort 3

posaconazole DRUG

100mg delayed release tablet or other strength as locally available given orally

Also known as: Noxafil

Part 3 - DDI Cohort 1

midazolam DRUG

2mg/mL oral solution or in other strength as locally available

Also known as: midazolam HCl

Part 3 - DDI Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasm, Residual

Interventions

siremadlin; Cytarabine; Anthracyclines; Daunorubicin; Idarubicin; midostaurin; posaconazole; Midazolam

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: November 13, 2018
• First Posted: November 30, 2018
• Study Start: November 15, 2019
• Primary Completion: July 22, 2021
• Study Completion: June 13, 2023
• Last Updated: January 9, 2020

Record last verified: 2020-01