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Leukemia, Myeloid, AcutePhase 1/2NCT03760445

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

A Phase 1/2 study testing HDM201, cytarabine and anthracycline in people with Leukemia, Myeloid, Acute, run by Novartis Pharmaceuticals.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Leukemia, Myeloid, Acute
What is being tested?
HDM201, cytarabine and anthracycline
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
15 Nov 2019to 13 Jun 2023
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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
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  • 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.

About this study

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)

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.

Read the detailed description

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

Being tested
HDM201, cytarabine, anthracycline, midostaurin, liposomal cytarabine/daunorubicin
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
Medical subject headings
Leukemia, Myeloid, Acute, Neoplasm, Residual

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • HDM201Drug

    Also called none available

    2.5 mg and 10mg capsules, given orally

  • cytarabineDrug

    Also called Ara-C, Cytosar

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

  • anthracyclineDrug

    Also called daunorubicin or idarubicin, Rubidomycin or Idamycin

    20mg or other strength as locally available given intravenously

  • midostaurinDrug

    Also called PKC412, Rydapt

    25mg capsules given orally

  • liposomal cytarabine/daunorubicinDrug

    Also called Vyxeos

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

  • posaconazoleDrug

    Also called Noxafil

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

  • midazolamDrug

    Also called midazolam HCl

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

Study groups in NCT03760445
Study groupRoleWhat they receive
Part 1 - first line (1L) AMLExperimental1L acute myeloid leukemia (AML) subjects receiving HDM201 in various doses/schedules in combination with cytarabine/anthracyclines
Receives: Drug: HDM201; Drug: cytarabine; Drug: anthracycline
Part 1 - relapsed/refractory (R/R) AMLExperimentalR/R AML subjects receiving HDM201 in various doses/schedules in combination with cytarabine
Receives: Drug: HDM201; Drug: cytarabine
Part 2 - Expansion Cohort 1Experimental1L de novo AML subjects without documented FLT3 mutation receiving HDM201 at the recommended dose of expansion (RDE) in combination with cytarabine/anthracyclines
Receives: Drug: HDM201; Drug: cytarabine; Drug: anthracycline
Part 2 - Expansion Cohort 2Experimental1L de novo AML subjects with documented FLT3 mutation status receiving HDM201 at RDE in combination with cytarabine/anthracyclines and midostaurin
Receives: Drug: HDM201; Drug: cytarabine; Drug: anthracycline; Drug: midostaurin
Part 2 - Expansion Cohort 3Experimental1L secondary AML subjects receiving HDM201 at RDE in combination with liposomal cytarabine/daunorubicin
Receives: Drug: HDM201; Drug: cytarabine; Drug: liposomal cytarabine/daunorubicin
Part 2 - Expansion Cohort 4ExperimentalR/R AML subjects receiving HDM201 at RDE in combination with cytarabine
Receives: Drug: HDM201; Drug: cytarabine
Part 3 - DDI Cohort 1ExperimentalR/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
Receives: Drug: HDM201; Drug: cytarabine; Drug: posaconazole
Part 3 - DDI Cohort 2ExperimentalR/R AML subjects receiving HDM201 at RP3D in combination with cytarabine and midazolam
Receives: Drug: HDM201; Drug: cytarabine; Drug: midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: first day of study treatment to 3 months after start of study treatment

  2. Part 1 - Time to DLT

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

    Measured: first day of study treatment to 3 months after start of study treatment

  3. 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

    Measured: first day of study treatment to 3 months after start of study treatment

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

    number and grade of AEs/SAEs by expansion cohort

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

  5. 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

    Measured: first day of study treatment until 4.5 months after start of study treatment

  6. Part 2 - Incidence and severity of abnormal laboratory values

    number and grade of abnormal laboratory results by expansion cohort

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

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

    number and severity of abnormal ECG results by expansion cohort

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

  8. Part 2 - Incidence and severity of abnormal vital signs

    number and severity of abnormal vital signs by expansion cohort

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

  9. 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

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

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

    determine HDM201 Cmax in Cycle 1

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

  11. Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration

    determine HDM201 average plasma concentration in Cycle 1

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

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

    determine HDM201 Tmax in Cycle 1

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

  13. Part 3 - DDI Cohort 2: midazolam PK AUC

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

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

  14. Part 3 - DDI Cohort 2: midazolam PK Cmax

    determine midazolam Cmax

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

Secondary outcomes (19)

  1. Part 1 +2: HDM201 PK AUC

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

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

  2. Part 1 +2: HDM201 PK Cmax

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

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

  3. Part 1 +2: HDM201 PK Tmax

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

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

  4. 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

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

  5. Part 2 - all Expansion Cohorts: time to platelet recovery

    determine time to platelet recovery by Expansion Cohort for each cycle

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

  6. Part 2 - all Expansion Cohorts: time to neutrophil recovery

    determine time to neutrophil recovery by Expansion Cohort for each cycle

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

  7. Part 2 - all Expansion Cohorts: overall survival

    determine overall survival by Expansion Cohort

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

  8. Part 2 - all Expansion Cohorts: event-free survival

    determine event-free survival by Expansion Cohort

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

  9. 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.

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

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

    determine DFS by Expansion Cohort

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

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

    determine CIR by Expansion Cohort

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

  12. 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

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

  13. 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

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

  14. Part 2 - expansion cohort 2: midostaurin PK AUC

    determine midostaurin AUC

    Measured: first day of study treatment to 7.5 month after start of study treatment

  15. Part 2 - expansion cohort 2: midostaurin PK Cmax

    determine midostaurin Cmax during induction and consolidation treatment

    Measured: first day of study treatment to 7.5 month after start of study treatment

  16. Part 2 - expansion cohort 2: midostaurin PK Tmax

    determine midostaurin Tmax during induction and consolidation treatment

    Measured: first day of study treatment to 7.5 month after start of study treatment

  17. 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

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

  18. 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

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

  19. 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

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Nov 2018
  2. Study start15 Nov 2019 (estimated)
  3. Primary completion22 Jul 2021 (estimated)
  4. Study completion13 Jun 2023 (estimated)

Why it stopped: It was determined that the study design may not be optimal given the changing AML treatment landscape.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
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).
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03760445
Sponsor's protocol ID
CHDM201A2101
Other IDs
2018-003107-19, 2018
Status last verified
Jan 2020
First submitted
13 Nov 2018
Last updated
9 Jan 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided: 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.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing HDM201, cytarabine and anthracycline in people with Leukemia, Myeloid, Acute, run by Novartis Pharmaceuticals.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 9 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part 1 - Incidence of dose limiting toxicity (DLT) (time frame: first day of study treatment to 3 months after start of study treatment). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03760445.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2020.

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