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

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)

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.

Study Overview

• Status: Withdrawn
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: HDM201; Drug: cytarabine; Drug: anthracycline; Drug: midostaurin; Drug: liposomal cytarabine/daunorubicin; Drug: posaconazole; Drug: midazolam

Detailed Description

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
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1 - first line (1L) AML; 1L acute myeloid leukemia (AML) subjects receiving HDM201 in various doses/schedules in combination with cytarabine/anthracyclines	Drug: HDM201; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar; Drug: anthracycline; 20mg or other strength as locally available given intravenously; Other Names: daunorubicin or idarubicin, Rubidomycin or Idamycin
EXPERIMENTAL: Part 1 - relapsed/refractory (R/R) AML; R/R AML subjects receiving HDM201 in various doses/schedules in combination with cytarabine	Drug: HDM201; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar
EXPERIMENTAL: Part 2 - Expansion Cohort 1; 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; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar; Drug: anthracycline; 20mg or other strength as locally available given intravenously; Other Names: daunorubicin or idarubicin, Rubidomycin or Idamycin
EXPERIMENTAL: Part 2 - Expansion Cohort 2; 1L de novo AML subjects with documented FLT3 mutation status receiving HDM201 at RDE in combination with cytarabine/anthracyclines and midostaurin	Drug: HDM201; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar; Drug: anthracycline; 20mg or other strength as locally available given intravenously; Other Names: daunorubicin or idarubicin, Rubidomycin or Idamycin; Drug: midostaurin; 25mg capsules given orally; Other Names: PKC412, Rydapt
EXPERIMENTAL: Part 2 - Expansion Cohort 3; 1L secondary AML subjects receiving HDM201 at RDE in combination with liposomal cytarabine/daunorubicin	Drug: HDM201; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar; Drug: liposomal cytarabine/daunorubicin; 100mg/44mg or other strength as locally available given intravenously; Other Names: Vyxeos
EXPERIMENTAL: Part 2 - Expansion Cohort 4; R/R AML subjects receiving HDM201 at RDE in combination with cytarabine	Drug: HDM201; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar
EXPERIMENTAL: Part 3 - DDI Cohort 1; 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; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar; Drug: posaconazole; 100mg delayed release tablet or other strength as locally available given orally; Other Names: Noxafil
EXPERIMENTAL: Part 3 - DDI Cohort 2; R/R AML subjects receiving HDM201 at RP3D in combination with cytarabine and midazolam	Drug: HDM201; 2.5 mg and 10mg capsules, given orally; Other Names: none available; Drug: cytarabine; 20mg or 1000 mg or other strengths as locally available given intravenously; Other Names: Ara-C, Cytosar; Drug: midazolam; 2mg/mL oral solution or in other strength as locally available; Other Names: midazolam HCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 +2: HDM201 PK AUC	determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2	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	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	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	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	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	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	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	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.	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	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	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	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	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	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	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	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	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	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	first day of study treatment to 8.5 months after start of study treatment

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): November 15, 2019
• Primary Completion (ANTICIPATED): July 22, 2021
• Study Completion (ANTICIPATED): June 13, 2023

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: November 28, 2018
• First Posted (ACTUAL): November 30, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 9, 2020
• Last Update Submitted That Met QC Criteria: January 6, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: idarubicin; HDM201; minimal residual disease; cytarabine; dose escalation; acute myeloid leukemia (AML); relapsed/refractory AML; combination treatment; midostaurin; daunorubicin; liposomal cytarabine/daunorubicin; 1L newly diagnosed AML; FLT3-mutation; CR/CRi; DDI with CYP3A4 inhibitors; DDI with sensitive CYP3A4 substrate
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Antiviral Agents; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antineoplastic; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Midazolam; Cytarabine; Daunorubicin; Idarubicin; Posaconazole; Midostaurin
• Other Study ID Numbers: CHDM201A2101; 2018-003107-19 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No