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

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ClinicalTrials.gov Identifier: NCT03760445
Recruitment Status : Recruiting
First Posted : November 30, 2018
Last Update Posted : August 9, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: HDM201 Drug: cytarabine Drug: anthracycline Drug: midostaurin Drug: liposomal cytarabine/daunorubicin Drug: posaconazole Drug: midazolam Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
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).

Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : September 4, 2019
Estimated Primary Completion Date : July 22, 2021
Estimated Study Completion Date : April 18, 2023


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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: Ara-C, Cytosar

Drug: anthracycline
20mg or other strength as locally available given intravenously
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: Ara-C, Cytosar

Drug: anthracycline
20mg or other strength as locally available given intravenously
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: Ara-C, Cytosar

Drug: anthracycline
20mg or other strength as locally available given intravenously
Other Name: daunorubicin or idarubicin, Rubidomycin or Idamycin

Drug: midostaurin
25mg capsules given orally
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: Ara-C, Cytosar

Drug: liposomal cytarabine/daunorubicin
100mg/44mg or other strength as locally available given intravenously
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: Ara-C, Cytosar

Drug: posaconazole
100mg delayed release tablet or other strength as locally available given orally
Other Name: 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 Name: none available

Drug: cytarabine
20mg or 1000 mg or other strengths as locally available given intravenously
Other Name: Ara-C, Cytosar

Drug: midazolam
2mg/mL oral solution or in other strength as locally available
Other Name: midazolam HCl




Primary Outcome Measures :
  1. Part 1 - Incidence of dose limiting toxicity (DLT) [ Time Frame: first day of study treatment to 3 months after start of study treatment ]
    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

  2. Part 1 - Time to DLT [ Time Frame: first day of study treatment to 3 months after start of study treatment ]
    time from first dose to onset of DLT by dose regimen of 1L AML and R/R AML subjects

  3. Part 1 - Incidence and severity of Adverse Events (AEs) [ Time Frame: first day of study treatment to 3 months after start of study treatment ]
    number and grade of AEs by dose regimen of 1L AML and R/R AML subjects during DLT observation period

  4. Part 2 - Incidence and severity of AEs/serious adverse events (SAEs) [ Time Frame: first day of study treatment until 8.5 months after start of study treatment ]
    number and grade of AEs/SAEs by expansion cohort

  5. Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR) [ Time Frame: first day of study treatment until 4.5 months after start of study treatment ]
    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

  6. Part 2 - Incidence and severity of abnormal laboratory values [ Time Frame: first day of study treatment until 8.5 months after start of study treatment ]
    number and grade of abnormal laboratory results by expansion cohort

  7. Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results [ Time Frame: first day of study treatment until 8.5 months after start of study treatment ]
    number and severity of abnormal ECG results by expansion cohort

  8. Part 2 - Incidence and severity of abnormal vital signs [ Time Frame: first day of study treatment until 8.5 months after start of study treatment ]
    number and severity of abnormal vital signs by expansion cohort

  9. Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC) [ Time Frame: first day of HDM201 dose to 10 days after start of HDM201 ]
    determine HDM201 AUC from time zero to the last measurable concentration sampling time (AUClast) in Cycle 1

  10. Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax) [ Time Frame: first day of HDM201 dose to 10 days after start of HDM201 ]
    determine HDM201 Cmax in Cycle 1

  11. Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration [ Time Frame: first day of HDM201 dose to 10 days after start of HDM201 ]
    determine HDM201 average plasma concentration in Cycle 1

  12. Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax) [ Time Frame: first day of HDM201 dose to 10 days after start of HDM201 ]
    determine HDM201 Tmax in Cycle 1

  13. Part 3 - DDI Cohort 2: midazolam PK AUC [ Time Frame: first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201) ]
    determine midazolam AUC last and AUC from time zero to infinity (inf)

  14. Part 3 - DDI Cohort 2: midazolam PK Cmax [ Time Frame: first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201) ]
    determine midazolam Cmax


Secondary Outcome Measures :
  1. Part 1 +2: HDM201 PK AUC [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2

  2. Part 1 +2: HDM201 PK Cmax [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    determine Cmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2

  3. Part 1 +2: HDM201 PK Tmax [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    determine Tmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2

  4. Part 1 - incidence of AEs/SAEs [ Time Frame: first day of study treatment to 8.5 months after start of study treatment ]
    number and grade of AEs/SAEs, by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

  5. Part 2 - all Expansion Cohorts: time to platelet recovery [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    determine time to platelet recovery by Expansion Cohort for each cycle

  6. Part 2 - all Expansion Cohorts: time to neutrophil recovery [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    determine time to neutrophil recovery by Expansion Cohort for each cycle

  7. Part 2 - all Expansion Cohorts: overall survival [ Time Frame: first day of study treatment to 3 years after last patient is enrolled to Part 2 ]
    determine overall survival by Expansion Cohort

  8. Part 2 - all Expansion Cohorts: event-free survival [ Time Frame: first day of study treatment to 3 years after last patient is enrolled to Part 2 ]
    determine event-free survival by Expansion Cohort

  9. Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT) [ Time Frame: first day of study treatment to 3 years after last patient was enrolled to Part 2 ]
    percentage of subjects receiving HSCT after study treatment by Expansion Cohort.

  10. Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS) [ Time Frame: first day of study treatment to 3 years after last patient enrolled to Part 2 ]
    determine DFS by Expansion Cohort

  11. Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR) [ Time Frame: first day of study treatment to 3 years after last patient enrolled to Part 2 ]
    determine CIR by Expansion Cohort

  12. Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    proportion of subjects achieving CR or CRi with ABCR by Expansion Cohort

  13. Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity [ Time Frame: first day of study treatment to 7.5 months after start of study treatment ]
    proportion of subjects achieving MRD negativity by Expansion Cohort

  14. Part 2 - expansion cohort 2: midostaurin PK AUC [ Time Frame: first day of study treatment to 7.5 month after start of study treatment ]
    determine midostaurin AUC

  15. Part 2 - expansion cohort 2: midostaurin PK Cmax [ Time Frame: first day of study treatment to 7.5 month after start of study treatment ]
    determine midostaurin Cmax during induction and consolidation treatment

  16. Part 2 - expansion cohort 2: midostaurin PK Tmax [ Time Frame: first day of study treatment to 7.5 month after start of study treatment ]
    determine midostaurin Tmax during induction and consolidation treatment

  17. Part 1 - incidence of abnormal laboratory values [ Time Frame: first day of study treatment to 8.5 months after start of study treatment ]
    number of abnormal laboratory results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

  18. Part 1 - incidence of abnormal ECG results [ Time Frame: first day of study treatment to 8.5 months after start of study treatment ]
    number of abnormal ECG results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days

  19. Part 1 - incidence of abnormal vital signs [ Time Frame: first day of study treatment to 8.5 months after start of study treatment ]
    number of abnormal vital signs by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03760445


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Israel
Novartis Investigative Site Recruiting
Tel Aviv, Israel, 6423906
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03760445     History of Changes
Other Study ID Numbers: CHDM201A2101
2018-003107-19 ( EudraCT Number )
First Posted: November 30, 2018    Key Record Dates
Last Update Posted: August 9, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Posaconazole
Daunorubicin
Idarubicin
Midostaurin
Midazolam
Staurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics