Leukemia
Conditions
Keywords
Aggressive systemic mastocytosis, mast cell leukemia, C-Findings, tyrosine kinase inhibitor, KIT mutation, AHNMD, Systemic, Aggressive
Brief summary
The purpose of this study was to determine the efficacy and safety of twice daily (bid) oral midostaurin in patients with Aggressive Systemic Mastocytosis (ASM) or Mast Cell Leukemia (MCL) with or without an Associated Hematological clonal Non-Mast cell lineage Disease (AHNMD).
Interventions
Midostaurin was provided as 25 mg soft gelatin capsules for oral administration.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: * Patients ≥ 18 years of age who provided written informed consent, Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 and a life expectancy of \>12 weeks, electrocardiogram with a QTcF of ≤ 450 ms, with a diagnosis of SM and sub-variants based on WHO criteria. * Patients with ASM or MCL were to have one or more measurable clinical findings (termed C-findings) and defined as those attributable to the mast cell disease component and not to AHNMD or any other cause. * Patients with MCL were to have BM aspirate smears with ≥ 20% immature MCs. Patients with AHNMD were eligible if it was not life-threatening or in an acute stage. Key
Exclusion criteria
* Patients with cardiovascular disease including congestive heart failure class III or IV according to the New York Heart Association classification, left ventricular ejection fraction (LVEF) of \<50%, myocardial infarction within the previous 6 months, or poorly controlled hypertension. * Patients with a heart block of any degree at screening (for Canada only). * Patients with an AHNMD who required immediate cytoreductive therapy or targeted therapy (other than midostaurin). * Patients who had demonstrated relapse after 3 or more prior regimens of SM treatment regardless of treatment regimen for supportive care (e.g., symptom-limiting therapies). * Patients who had received any investigational agent, targeted therapy, chemotherapy, interferon-α, or 2 chlorodeoxyadenosine within 30 days prior to start of midostaurin treatment. * Patients who had ASM with eosinophilia and known positivity for the FIP1L1- PDGFRα fusion unless they had demonstrated relapse or disease progression on prior imatinib therapy. * Patients who had received any treatment with midostaurin prior to study entry. * Patients who had received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment. * Patients who had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1 of midostaurin treatment. * Patients with any pulmonary infiltrate, including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray were not eligible until the pulmonary infiltrates had completely resolved. Exception: patients with ASM/MCL ± AHNMD-related pleural effusion as judged by the Investigator and approved by the SSC Chairperson or designee were permitted to enter the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response Rate (ORR) | 6 months | Overall Response Rate (ORR) was defined as the percentage of participants who classified as confirmed responders (Major Response (MR) or Partial Response (PR)) by the adjudication of the SSC and based on a Modified Valent Criteria. A major responder had complete resolution of at least one C-Finding and no progression in other C-Findings. A partial responder showed a measurable improvement in one or more C-Finding(s) without confirmed progression in other C-Findings. A C-Finding was a Clinical Finding, which was considered by the investigator and corroborated by the Study Steering Committee (SSC) Chairperson or designee, attributable to the mast cell disease component and not the associated hematological clonal non-mast cell lineage disease (AHNMD) component or any other cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Response (TTR) | Up 5 years | The Time to response (TTR) was defined as the time from start of treatment until the date of onset of confirmed response (MR or PR). |
| Median Time to Progression-Free Survival (PFS) | Up 5 years | The Progression-free survival (PFS) is defined as the time from start of treatment to the date of the first documented and confirmed progression or death due to any cause. |
| Median Time to Duration of Response (DoR) | Up 5 years | The Duration of response (DoR) was defined as the time from first onset of confirmed response (MR or PR) to the date of first documented and confirmed progression or death due to ASM/MCL. |
| Long-term Safety and Tolerability of Midostaurin | Up to 30 days after last dose of study treatment | Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) |
| Histopathologic Response | Up 5 years | Histopathologic response was summarized to demonstrate the change from baseline in percentage of mast cell infiltrations in the Bone Marrow (BM) and related serum tryptase levels. |
| Median Time to Overall Survival (OS) | Up 5 years | The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Netherlands, Norway, Poland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 29 centers in 12 countries worldwide (Australia, Austria, Belgium, Canada, France, Germany, Netherlands, Norway, Poland, Turkey, United Kingdom, United States).
Pre-assignment details
The Participant Flow was on the Full Analysis Set (FAS), the Baseline Characteristics were done on the FAS and Primary Efficacy Population (PEP). The Efficacy analysis was done on the PEP (except for the Overall Survival which was done on FAS and PEP). The Safety analysis was done on the Safety Set (SS).
Participants by arm
| Arm | Count |
|---|---|
| Midostaurin (PKC412) Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first. | 116 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative problems | 14 |
| Overall Study | Adverse Event | 35 |
| Overall Study | Death | 9 |
| Overall Study | Disease progression | 43 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Protocol deviation | 2 |
| Overall Study | Subject withdrew consent | 11 |
Baseline characteristics
| Characteristic | Midostaurin (PKC412) |
|---|---|
| Age, Continuous | 61.8 Years STANDARD_DEVIATION 11.76 |
| Age Continuous (PEP) | 63.0 Years STANDARD_DEVIATION 11.59 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 111 Participants |
| Race (PEP) PEP (n=89) - Black | 1 Participants |
| Race (PEP) PEP (n=89) - Other/Missing | 2 Participants |
| Race (PEP) PEP (n=89) - White | 86 Participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 76 Participants |
| Sex: Female, Male (PEP) PEP (n=89) - Female | 32 Participants |
| Sex: Female, Male (PEP) PEP (n=89) - Male | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 25 / 116 |
| other Total, other adverse events | 115 / 116 |
| serious Total, serious adverse events | 88 / 116 |
Outcome results
Primary
Percentage of Participants With Overall Response Rate (ORR)
Overall Response Rate (ORR) was defined as the percentage of participants who classified as confirmed responders (Major Response (MR) or Partial Response (PR)) by the adjudication of the SSC and based on a Modified Valent Criteria. A major responder had complete resolution of at least one C-Finding and no progression in other C-Findings. A partial responder showed a measurable improvement in one or more C-Finding(s) without confirmed progression in other C-Findings. A C-Finding was a Clinical Finding, which was considered by the investigator and corroborated by the Study Steering Committee (SSC) Chairperson or designee, attributable to the mast cell disease component and not the associated hematological clonal non-mast cell lineage disease (AHNMD) component or any other cause.
Time frame: 6 months
Population: Primary Efficacy Population: participants assigned to study treatment who met diagnostic criteria for aggressive systemic mastocytosis or mast cell leukemia and presented with at least 1 measurable C-Finding at study entry and/or participants with transfusion dependent anemia due to their underlying disease at study entry as confirmed by the SCC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Midostaurin (PKC412) | Percentage of Participants With Overall Response Rate (ORR) | 59.6 Percentage of participants |
p-value: <0.001Exact Binomial Test
Secondary
Histopathologic Response
Histopathologic response was summarized to demonstrate the change from baseline in percentage of mast cell infiltrations in the Bone Marrow (BM) and related serum tryptase levels.
Time frame: Up 5 years
Population: Primary Efficacy Population (PEP); for each patient, the best improvement relative to Baseline was considered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midostaurin (PKC412) | Histopathologic Response | >50% decrease in mast cell (MC) (n=41) | 46.1 Percentage of participants |
| Midostaurin (PKC412) | Histopathologic Response | >0-<=50% decrease in mast cell (MC) (n=19) | 21.3 Percentage of participants |
| Midostaurin (PKC412) | Histopathologic Response | >50% decrease in serum tryptase (n=52) | 58.4 Percentage of participants |
| Midostaurin (PKC412) | Histopathologic Response | >0-<=50% decrease in serum tryptase (n=25) | 28.1 Percentage of participants |
Secondary
Long-term Safety and Tolerability of Midostaurin
Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC)
Time frame: Up to 30 days after last dose of study treatment
Population: Safety Set (SS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midostaurin (PKC412) | Long-term Safety and Tolerability of Midostaurin | AEs by Primary System Organ Class (SOC) (n=116) | 100 Percentage of participants |
| Midostaurin (PKC412) | Long-term Safety and Tolerability of Midostaurin | SAEs by Primary System Organ Class (SOC) (n=88) | 75.9 Percentage of participants |
| Midostaurin (PKC412) | Long-term Safety and Tolerability of Midostaurin | Deaths by Primary System Organ Class (SOC) (n=25) | 21.6 Percentage of participants |
Secondary
Median Time to Duration of Response (DoR)
The Duration of response (DoR) was defined as the time from first onset of confirmed response (MR or PR) to the date of first documented and confirmed progression or death due to ASM/MCL.
Time frame: Up 5 years
Population: Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midostaurin (PKC412) | Median Time to Duration of Response (DoR) | 31.4 Months |
Secondary
Median Time to Overall Survival (OS)
The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause.
Time frame: Up 5 years
Population: Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response and the Full Analysis Set (FAS), which consisted of all patients who received at least one dose of study drug were considered.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midostaurin (PKC412) | Median Time to Overall Survival (OS) | Primary Efficacy Population (PEP) (n=89) | 26.8 Months |
| Midostaurin (PKC412) | Median Time to Overall Survival (OS) | Full Analysis Set (FAS) (n=116) | 28.7 Months |
Secondary
Median Time to Progression-Free Survival (PFS)
The Progression-free survival (PFS) is defined as the time from start of treatment to the date of the first documented and confirmed progression or death due to any cause.
Time frame: Up 5 years
Population: Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midostaurin (PKC412) | Median Time to Progression-Free Survival (PFS) | 17.0 Months |
Secondary
Median Time to Response (TTR)
The Time to response (TTR) was defined as the time from start of treatment until the date of onset of confirmed response (MR or PR).
Time frame: Up 5 years
Population: Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midostaurin (PKC412) | Median Time to Response (TTR) | 0.3 Months |