Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Midostaurin

Protein Kinase Inhibitors

Enzyme Inhibitors

midostaurin 50 mg (two 25 mg capsules) is given in combination with the second of two induction cycles and in combination with three cycles of high-dose cytarabine (HiDAC) consolidation chemotherapies and maintenance treatment in patients with c-kit or FLT3-ITD positive t(8;21) AML in an open-label one-arm design. The first cycle of induction is not part of the study.

Midostaurin 50 mg (2 capsules) twice daily days 8-21 in induction II + consolidation I-III; maintenance treatment twice daily continuously for 12 months

midostaurin (PKC412)

Christoph Röllig, Prof. Dr.

To assess the efficacy of tyrosine-kinase inhibitor midostaurin in c-KIT or FLT3-ITD mutated t(8;21) AML. To assess the efficacy of midostaurin depending on the type of c-KIT mutation

AML patients displaying t(8;21) have a relatively favourable outcome. Nevertheless, only approximately 50% of patients carrying this cytogenetic aberration are alive at 5 years. This suggests that some patients have more aggressive leukemic phenotypes and indicates the need for treatment optimization with novel therapies.

The mutated KIT gene as well as the FLT3-ITD mutation have recently been identified as factors most likely to explain the heterogeneous clinical outcomes within the group of t(8;21) AML. The FLT3 and c-KIT genes encode type III receptor tyrosine kinases (RTK) with important and partly redundant functions in early hematopoietic stem cells. Various activating mutations have been described for both genes. For c-KIT, the incidence ranges from 17 to 48% depending on the source population and type of mutations determined. It has been consistently shown that in AMLs with t(8;21), mutated c-KIT is associated with a dramatically increased risk of relapse and reduced overall survival compared to their unmutated counterparts. The FLT3-ITD mutation has a similar negative effect on prognosis in the patient group of t(8;21) mutated AMLs as c-KIT.

PKC412 (midostaurin) is known to inhibit the c-KIT RTK activity as well as the FLT3 kinase, both in patients with ITD and TKD mutations. It should therefore be possible to abrogate the negative impact of pathologically increased c-KIT or FLT3-ITD activity on relapse and overall survival by using midostaurin in this patient population. Aim of the proposed clinical trial is to prove the efficacy of midostaurin in c-KIT or FLT3-ITD mutated t(8;21)- AMLs in an open-label one-arm design.

Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML

A Single-arm Phase II Trial to Assess the Efficacy of Midostaurin (PKC412) Added to Standard Primary Therapy in Patients With Newly Diagnosed c-KIT or FLT3-ITD Mutated t(8;21) AML

molecular diagnostics of markers in peripheral blood / bone marrow

Novartis Pharmaceuticals

Technische Universität Dresden

Immune System Diseases

Behaviors and Mental Disorders

Nervous System Diseases

Skin and Connective Tissue Diseases

Mastocytosis

Aggression

Mastocytosis, Systemic

Leukemia, Mast-Cell

Dementia

Aberrant Motor Behavior in Dementia

Behavioral Symptoms

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Mast Cell Activation Disorders

Systemic Mastocytosis

Amino Acids

Tyrosine Kinase Inhibitors

Tyrosine

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.

Midostaurin was provided as 25 mg soft gelatin capsules for oral administration.

Midostaurin (PKC412)

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).

Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia

A Single Arm, Phase II, Open-Label Study to Determine the Efficacy of 100mg Twice Daily Oral Dosing of Midostaurin Administered to Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease

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 review 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 availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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.

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).

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.

The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause.

Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC)

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.

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Age Continuous (PEP)

PEP (n=89) - Female

PEP (n=89) - Male

Sex: Female, Male (PEP)

PEP (n=89) - Black

PEP (n=89) - White

PEP (n=89) - Other/Missing

Race (PEP)

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).

Study Director

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.

Percentage of Participants With Overall Response Rate (ORR)

Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.

Median Time to Duration of Response (DoR)

Median Time to Response (TTR)

Median Time to Progression-Free Survival (PFS)

Primary Efficacy Population (PEP) (n=89)

Full Analysis Set (FAS) (n=116)

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.

Median Time to Overall Survival (OS)

AEs by Primary System Organ Class (SOC) (n=116)

SAEs by Primary System Organ Class (SOC) (n=88)

Deaths by Primary System Organ Class (SOC) (n=25)

Long-term Safety and Tolerability of Midostaurin

>50% decrease in mast cell (MC) (n=41)

>0-<=50% decrease in mast cell (MC) (n=19)

>50% decrease in serum tryptase (n=52)

>0-<=50% decrease in serum tryptase (n=25)

Primary Efficacy Population (PEP); for each patient, the best improvement relative to Baseline was considered.

Histopathologic Response

Overall Study

Daunorubicin

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Induction therapy: 50 mg, oral, twice daily, starting on day 8, thereafter continuous dosing until 48h before start of subsequent chemotherapy cycle.

Consolidation therapy: 50 mg, oral twice daily, starting on day 6, thereafter continuous dosing until 48h before start of conditioning therapy for allogeneic HSCT or 48h before start of subsequent consolidation chemotherapy.

Maintenance therapy:

50 mg oral twice daily over one year.

Induction therapy:

200 mg/m2/day by continuous i.v. infusion on days 1-7 (total dose 1400 mg/m²)

Consolidation therapy:

Younger adult patients (18 to 65 yrs): 3 g/m2 by i.v infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 18 g/m2).

Older patients (\>65 yrs): 1 g/m2 by i.v. infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 6 g/m2).

Induction therapy:

60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²)

Hartmut Doehner, MD

This is a phase II, single-arm, open-label, multi-center study in adult patients with Acute Myeloid Leukemia (AML) and FLT3-ITD as defined in inclusion/exclusion criteria.

The primary efficacy object is to evaluate the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.

Sample size: 440 patients

The treatment duration of an individual patient is between 18 and 24 months. Duration of the study for an individual patient including treatment (induction, consolidation \[chemotherapy or allogeneic SCT\], maintenance and follow-up period: Maximum 8 years

Protocol in Acute Myeloid Leukemia With FLT3-ITD

Phase-II Study Evaluating Midostaurin in Induction, Consolidation and Maintenance Therapy Also After Allogeneic Blood Stem Cell Transplantation in Patients With Newly Diagnosed Acute Myeloid Leukemia Exhibiting a FLT3 Internal Tandem Duplication

To perform two predefined subgroup analyses in the age-groups 18-60 years and 61-70 years evaluating the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.

Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin

Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics initially, in first CR, after one year,3 and 5 years after initial diagnosis.

Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 3.0), timing and relatedness of hematological and non-hematological toxicities observed during the different treatment cycles

Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML	NCT01830361	Acute Myeloid L...	midostaurin (PK...	18 Years - 65 Years	Technische Universität Dresden
Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia	NCT00782067	Leukemia	Midostaurin (PK...	18 Years -	Novartis
Protocol in Acute Myeloid Leukemia With FLT3-ITD	NCT01477606	Acute Myeloid L...	Midostaurin Cytarabine Daunorubicin	18 Years - 70 Years	University of Ulm
Protocol in Acute Myeloid Leukemia With FLT3-ITD	NCT01477606	Acute Myeloid L...	Midostaurin Cytarabine Daunorubicin	18 Years - 70 Years	University of Ulm
Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML	NCT01830361	Acute Myeloid L...	midostaurin (PK...	18 Years - 65 Years	Technische Universität Dresden

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