AML, AdultPhase 1HDMMNCT04496999
HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt.
A Phase 1 study testing HDM201 and Midostaurin in people with AML, Adult, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
Trial summary
This is a non-randomized prospective open-label single-arm clinical phase I trial investigating dose finding, feasibility and safety of the combined treatment of HDM201 and midostaurin in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3mut applying an accelerated titration design. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- AML, Adult
- What is being tested?
- HDM201 and Midostaurin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteSwitzerland
- Study dates
- 13 Jul 2020to 9 Sep 2022
- Phase
- Phase 1
- 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
- AML with FLT3-ITD or FLT3-TKD and TP53wt.
- Age over 18 years
- Patient must give written informed consent before registration indicating that the patient understands the purpose of the procedures required for the trial and is willing to participate in the trial.
- Patients with relapsed/refractory disease must have morphologic proof (from bone marrow aspirate, smears or touch preps of bone marrow biopsy) of AML with >= 10% blasts within two weeks (14 days) prior to initiation of therapy.
- Patients must demonstrate one of the following: Relapse after first complete remission or refractory to conventional induction chemotherapy with or without Midostaurin (failure to respond to 1 or more cycles of daunorubicin and cytarabine) or to re-induction.
- Patients with relapse after HSCT (non-preventive) and pretransplant treatment with Midostaurin (FLT3-ITD or FLT3-TKD at diagnosis) or without Midostaurin (acquired FLT3 mutation).
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- Laboratory values that indicate adequate organ function assessed locally at the screening visit:
- AST ≤ 3 times ULN
- Alanine aminotransferase (ALT) ≤ 3 times ULN
- Serum total bilirubin ≤ 1.5 times ULN, unless in case of hyperbilirubinemia due to an isolated Gilbert syndrome
- Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30ml/min
- ECOG score performance status 0-2.
- Patients may have received therapy for other malignancies, as long as they have completed therapy at least 6 months prior to study entry.
- Subjects must have a life expectancy of 3 or more months.
Who cannot join
- AML with FLT3wt or TP53mut
- Ongoing adverse event drug-induced neuropathy of prior therapy grade ≥2 (according to CTCAE criteria Version 5.0) at registration
- Previous malignancy within 2 years with the exception of adequately treated in situ cervical cancer or localized non-melanoma skin cancer.
- Evidence of ongoing uncontrolled systemic infections.
- Major surgery within 4 weeks prior to trial registration
- Concurrent treatment with other experimental drugs or treatment in a clinical trial within 30 days prior to trial registration.
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- Treatment with chemotherapy and radiotherapy within 3 weeks prior to trial registration
- Vaccinated with live, attenuated vaccines within 4 weeks prior to trial registration
- History of stroke or intracranial hemorrhage within 6 months prior to trial registration.
- Clinically significant cardiovascular disease such as congestive heart failure NYHA III or IV (as defined by the New York Heart Association Functional Classification), uncontrolled or symptomatic arrhythmias, unstable angina pectoris, myocardial infarction within 6 months of prior to registration
- Prior solid organ transplantation
- Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion,
- could impair the ability of the patient to participate in the trial
- could compromise the patient's safety,
- could interfere with the absorption or metabolism of midostaurin or HDM201,
- could put the trial outcomes at undue risk,
- could prevent compliance with trial treatment.
- Psychiatric disorder precluding understanding of trial information, giving informed consent, or interfering with compliance for oral drug intake.
- Known hypersensitivity to trial drug(s) or hypersensitivity to any other component of the trial drugs.
- Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up.
- Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin and/or HDM201.
- Known confirmed diagnosis of HIV infection or active viral hepatitis (testing is not mandatory to exclude these viral infections).
- Pregnant or nursing (lactating) women
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 12 months after stopping medication. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 12 months prior to screening). The vasectomized male partner should be the sole partner for that subject
- Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
- Midostaurin may reduce the effectiveness of hormonal contraceptives; therefore, females using systemically active hormonal contraceptives should add a barrier method of contraception.
- Women are considered post-menopausal and not of child bearing potential if they have had 2 years of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
- Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for at least 12 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.
- Unwillingness or inability to comply with the protocol.
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
Departement of Medical Oncology, University Hospital Berne
Bern, 3010
About this study
Official title: HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt; a Phase I Study.
This is a non-randomized prospective open-label single-arm clinical phase I trial investigating dose finding, feasibility and safety of the combined treatment of HDM201 and midostaurin in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3mut applying an accelerated titration design.
Read the detailed description
Background and Rationale:
Acute myeloid leukemia (AML) is a clonal hematopoietic malignant disease characterized by genetic and epigenetic alterations leading to inactivation of the tumor suppressor p53. This contributes to a block in normal differentiation of the various blood type lineages and to an accumulation of leukemic blasts in the blood and bone marrow. The disease variants have been grouped into favorable, intermediate and poor risk categories. The largest group of poor risk AML is characterized by the genetic alterations of the FLT3 receptor gene termed FLT3-ITD or FLT3-TKD. The prognosis for this specific subset which comprises 25-35% of all AML patients is generally poor, particularly in elderly or in relapsed patients, highlighting the unmet need for novel treatments.
Targeting the mutated FLT3 receptor is a promising approach to treat this specific poor risk AML subset. Midostaurin is particularly effective to induce cell death in FLT3-ITD/-TKD and TP53wt cells. Targeting MDM2 is a novel approach to restore the crucial p53 tumor suppressor function in AML cells. Preliminary data indicate that the MDM2 inhibitor HDM201 is active in AML cell lines in vitro and in vivo. Like midostaurin HDM201 is specifically effective to induce cell death in FLT3-ITD and TP53wt cells. The combination of midostaurin and HDM201 targets FLT3-ITD AML cells, with little effect on FLT3 wt cells and healthy blood cells. Both compounds induce apoptosis and cell death in a dose-dependent manner in FLT3-ITD TP53wt AML cells, with enhanced effects in the combination treatment. The combination treatment with midostaurin and HDM201 ought to be superior to the current best available treatment which utilizes intensive genotoxic induction therapy. In order to confirm inhibition of mutated FLT3 receptor and restoration of p53 tumor suppressor function, blood samples will be analyzed in this trial before, during and after treatment with HDM201 and midostaurin for changes in the expression of FLT3 and p53 target genes as well as induction of pro- apoptotic genes. These gene expression levels will be correlated with clinical response and outcome.
Objectives:
Primary objective:
The primary objective of this trial is to establish the recommended dose for a subsequent phase II (RP2D) of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML.
Secondary objectives:
The secondary objectives are to determine the safety and tolerability of HDM201 in combination with midostaurin and to assess the preliminary antitumor activity of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML and in newly diagnosed AML with FLT3mut and TP53wt.
Study Duration:
The trial study duration encompasses the time from when the first participant signs the informed consent until the last protocol-specific procedure of the last patient in the trial has been completed.
This phase I trial involves a minimum of 3 and a maximum of 24 subjects. Accordingly, the Investigator anticipate a duration of recruitment of between 3 and 18 months.
All patients will be followed up for up to 12 months after end of treatment, adding to a total study duration of between 15 and 33 months depending on the effective number of patients in the various dose cohorts.
- Conditions
- AML, Adult
- Being tested
- HDM201, Midostaurin
- Keywords
- AML with FLT3-ITD or FLT3-TKD and TP53wt, relapsed/refractory AML
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HDM201Drug
Also called Dose finding
Dose level 0: HDM201 40 mg QD d1,2 (midday)/ Dose level 1: HDM201 40 mg QD d1,2,3 (midday) = Starting dose/ Dose level 2: HDM201 40 mg QD d1,2,3,4,5 (midday)/ Dose level 3: HDM201 60 mg QD d1,2,3,4,5 (midday)/ Dose level 4: HDM201 80 mg QD d1,2,3,4,5 (midday)
MidostaurinDrug
Midostaurin 50mg bid d1-28 (morning, evening)
| Study group | Role | What they receive |
|---|---|---|
| Midostaurin with HDM201 dose escalation. | Experimental | Midostaurin 50mg bid d1-28 (morning, evening) and HDM201 Receives: Drug: HDM201; Drug: Midostaurin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose finding
to identify the incidence of dose limiting toxicities (DLT) at each dose level and to determine the maximum tolerated dose (MTD) of HDM201 and its recommended dose that will be used in a later phase II study (recommended phase II dose; RP2D) when added to midostaurin
Measured: 30 days
Secondary outcomes (5)
Overall response rate (ORR)
CR, CRi, CRp, PR including assessment of minimal residual disease by molecular diagnostics and flowcytometry after cycles 1 and 2.
Measured: 60 days
Adverse Events
Number of patients experiencing adverse events and severity of the adverse events
Measured: 33 months
Progression free survival
Time from end of treatment (after bone marrow assessment after cycle 2) until progression of disease or death as a result of any cause.
Measured: 33 months
Overall survival
Time from end of treatment (after bone marrow assessment after cycle 2) until death as a result of any cause.
Measured: 33 months
Infectious complications of study treatment
Assessment of the number of febrile episodes requiring antibiotic/antifungal treatment as well as assessment of identified causing germs.
Measured: 33 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Aug 2020
- Study start13 Jul 2020
- Primary completion9 Sep 2022
- Study completion9 Sep 2022
Why it stopped: Insufficient recruitment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AML, AdultStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Non-randomized prospective open-label single-arm clinical phase I trial investigating dose finding, feasibility and safety of the combined treatment of HDM201 and midostaurin
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas Pabst, Prof, Study chair, Department of Medical Oncology, University Hospital Bern Switzerland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04496999
- Sponsor's protocol ID
- HDMM
- Acronym
- HDMM
- Status last verified
- Oct 2022
- First submitted
- 29 Jul 2020
- Last updated
- 6 Oct 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt; a Phase I Study.
- ClinicalTrials.gov ID
- NCT04496999
- Acronym / sponsor ID
- HDMM / HDMM
- Conditions
- AML, Adult
- Keywords
- AML with FLT3-ITD or FLT3-TKD and TP53wt, relapsed/refractory AML
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Insufficient recruitment
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Study start
- 13 Jul 2020 (actual)
- Primary completion
- 9 Sep 2022 (actual)
- Study completion
- 9 Sep 2022 (actual)
- First posted
- 4 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a non-randomized prospective open-label single-arm clinical phase I trial investigating dose finding, feasibility and safety of the combined treatment of HDM201 and midostaurin in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3mut applying an accelerated titration design.
Detailed description
Background and Rationale:
Acute myeloid leukemia (AML) is a clonal hematopoietic malignant disease characterized by genetic and epigenetic alterations leading to inactivation of the tumor suppressor p53. This contributes to a block in normal differentiation of the various blood type lineages and to an accumulation of leukemic blasts in the blood and bone marrow. The disease variants have been grouped into favorable, intermediate and poor risk categories. The largest group of poor risk AML is characterized by the genetic alterations of the FLT3 receptor gene termed FLT3-ITD or FLT3-TKD. The prognosis for this specific subset which comprises 25-35% of all AML patients is generally poor, particularly in elderly or in relapsed patients, highlighting the unmet need for novel treatments.
Targeting the mutated FLT3 receptor is a promising approach to treat this specific poor risk AML subset. Midostaurin is particularly effective to induce cell death in FLT3-ITD/-TKD and TP53wt cells. Targeting MDM2 is a novel approach to restore the crucial p53 tumor suppressor function in AML cells. Preliminary data indicate that the MDM2 inhibitor HDM201 is active in AML cell lines in vitro and in vivo. Like midostaurin HDM201 is specifically effective to induce cell death in FLT3-ITD and TP53wt cells. The combination of midostaurin and HDM201 targets FLT3-ITD AML cells, with little effect on FLT3 wt cells and healthy blood cells. Both compounds induce apoptosis and cell death in a dose-dependent manner in FLT3-ITD TP53wt AML cells, with enhanced effects in the combination treatment. The combination treatment with midostaurin and HDM201 ought to be superior to the current best available treatment which utilizes intensive genotoxic induction therapy. In order to confirm inhibition of mutated FLT3 receptor and restoration of p53 tumor suppressor function, blood samples will be analyzed in this trial before, during and after treatment with HDM201 and midostaurin for changes in the expression of FLT3 and p53 target genes as well as induction of pro- apoptotic genes. These gene expression levels will be correlated with clinical response and outcome.
Objectives:
Primary objective:
The primary objective of this trial is to establish the recommended dose for a subsequent phase II (RP2D) of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML.
Secondary objectives:
The secondary objectives are to determine the safety and tolerability of HDM201 in combination with midostaurin and to assess the preliminary antitumor activity of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML and in newly diagnosed AML with FLT3mut and TP53wt.
Study Duration:
The trial study duration encompasses the time from when the first participant signs the informed consent until the last protocol-specific procedure of the last patient in the trial has been completed.
This phase I trial involves a minimum of 3 and a maximum of 24 subjects. Accordingly, the Investigator anticipate a duration of recruitment of between 3 and 18 months.
All patients will be followed up for up to 12 months after end of treatment, adding to a total study duration of between 15 and 33 months depending on the effective number of patients in the various dose cohorts.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Non-randomized prospective open-label single-arm clinical phase I trial investigating dose finding, feasibility and safety of the combined treatment of HDM201 and midostaurin
| Arm | Type | Receives |
|---|---|---|
| Midostaurin with HDM201 dose escalation. | Experimental | Drug: HDM201, Drug: MidostaurinMidostaurin 50mg bid d1-28 (morning, evening) and HDM201 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- AML with FLT3-ITD or FLT3-TKD and TP53wt.
- Age over 18 years
- Patient must give written informed consent before registration indicating that the patient understands the purpose of the procedures required for the trial and is willing to participate in the trial.
- Patients with relapsed/refractory disease must have morphologic proof (from bone marrow aspirate, smears or touch preps of bone marrow biopsy) of AML with >= 10% blasts within two weeks (14 days) prior to initiation of therapy.
- Patients must demonstrate one of the following: Relapse after first complete remission or refractory to conventional induction chemotherapy with or without Midostaurin (failure to respond to 1 or more cycles of daunorubicin and cytarabine) or to re-induction.
Key exclusion criteria (33 listed)
- AML with FLT3wt or TP53mut
- Ongoing adverse event drug-induced neuropathy of prior therapy grade ≥2 (according to CTCAE criteria Version 5.0) at registration
- Previous malignancy within 2 years with the exception of adequately treated in situ cervical cancer or localized non-melanoma skin cancer.
- Evidence of ongoing uncontrolled systemic infections.
- Major surgery within 4 weeks prior to trial registration
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HDM201Also: Dose findingDose level 0: HDM201 40 mg QD d1,2 (midday)/ Dose level 1: HDM201 40 mg QD d1,2,3 (midday) = Starting dose/ Dose level 2: HDM201 40 mg QD d1,2,3,4,5 (midday)/ Dose level 3: HDM201 60 mg QD d1,2,3,4,5 (midday)/ Dose level 4: HDM201 80 mg QD d1,2,3,4,5 (midday) | Drug | Midostaurin with HDM201 dose escalation. |
| MidostaurinMidostaurin 50mg bid d1-28 (morning, evening) | Drug | Midostaurin with HDM201 dose escalation. |
Primary outcome
Dose finding
Time frame: 30 days
to identify the incidence of dose limiting toxicities (DLT) at each dose level and to determine the maximum tolerated dose (MTD) of HDM201 and its recommended dose that will be used in a later phase II study (recommended phase II dose; RP2D) when added to midostaurin
5 secondary outcomes
Overall response rate (ORR)
Time frame: 60 days
Adverse Events
Time frame: 33 months
Progression free survival
Time frame: 33 months
Overall survival
Time frame: 33 months
Infectious complications of study treatment
Time frame: 33 months
Results and safety
The study was stopped early (reason given: Insufficient recruitment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2022.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Pabst, Prof study chair
Department of Medical Oncology, University Hospital Bern Switzerland
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing HDM201 and Midostaurin in people with AML, Adult, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
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 33 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: stopped early, as of the sponsor's last update on 6 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
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 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.
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 stopped early (reason given: Insufficient recruitment). Results are not available in the source record.
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?
Dose finding (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 6 Oct 2022.