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

Amino Acids

Cytarabine

Daunorubicin

Idarubicin

Midostaurin

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Protein Kinase Inhibitors

Tyrosine

Patients went through 3 phases:

Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles

Induction Phase: 50 mg (two 25 mg capsules) twice a day by mouth on days 8-28, for 1 - 2 cycles; a cycle = 28 days; Consolidation Phase: 50 mg (two 25 mg capsules) twice a day by mouth on days 8-28, for up to 4 cycles; Maintenance Phase: Continuous dosing (days 1 - 28) for up yo 12 cycles or until relapse, unacceptable toxicity, death, physician's decision, subject/guardian decision, protocol deviation, study termination by Sponsor, lost to follow-up, technical problems, pregnancy, subject withdrew consent, or until the end of study, whichever event occurred first.

Induction Phase (standard dose) (7 + 3 arm): 100-200 mg/m2/day by Continuous intravenous infusion (CIVI) days 1-7 (168 hours infusion); Induction Phase (5 + 2 arm): 100 mg/m2/day by CIVI days 1-5; Consolidation Phase: 1-3 g/m2 infusion over 3 hours every 12 h on days 1, 3 and 5, up to 4 cycles based on age and per investigator discretion

daunorubicin (7 + 3 arm): 60-90 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); daunorubicin (5 + 2 arm): 60 mg/m2/day by IV push on days 1-2; idarubicin (7 + 3 arm): 12 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); idarubicin (5 + 2 arm): 12 mg/m2/day by IV push on days 1-2

anthracycline ((daunorubicin or idarubicin): Induction Phase only

Novartis Pharmaceuticals

The purpose of this study was to gather and evaluate additional safety and efficacy data on the combination of midostaurin and standard of care for adult patients with newly diagnosed Fms-like tyrosine kinase receptor (FLT3) mutated Acute Myeloid Leukemia (AML) who were eligible for standard induction and consolidation

This Phase IIIb study was designed as a single arm study and allowed the assessment of variation of the "7+3" regimen in an extended patient population compared to RATIFY (higher dose of daunorubicin (60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), and lower dose of cytarabine (100-200 mg/m2/day) and the "5+2" reduced dose regimen). Safety was the primary endpoint. Complete Response (CR)/Complete remission with incomplete hematological recovery (CRi) in induction, consolidation and maintenance therapy was collected as secondary endpoint.

Patients who were newly diagnosed with AML, had a known FLT3 ITD (Internal tandem duplication) or TKD (Tyrosine kinase domain)(, mutation and had recently started on "7+3" or "5+2" in induction and high dose of cytarabine in consolidation were consented and screened for the clinical study.

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The protocol treatment allowed the following treatment phases:

* Induction Phase: cytarabine with anthracycline (idarubicin or daunorubicin) sequentially per HCP choice, followed by midostaurin on day 8. In the first Induction phase, a bone marrow aspiration was performed in all subjects on Days 21- 28 (according to local standard of care) to determine the need for a second induction cycle. If the marrow aspirate was inadequate to make a determination, the bone marrow assessment was repeated within one week. If the Day 21-28 (according to local standard of care) bone marrow aspiration reveals ≥ 5% leukemic blasts in a cellular marrow (\> 20%) a second induction was given. For subjects requiring a second induction, treatment began at least 3 days after completing midostaurin. Bone marrow aspiration was performed within one week after recovery of ANC ≥ 1000/μL and platelets ≥ 100,000/μL to assess for response. Subjects in CR proceeded to consolidation therapy. Subjects not achieving a marrow remission (or with persistent blasts) were to be removed from protocol therapy. Subjects with CRi proceeded to consolidation therapy as per investigator's discretion. 1 or 2 cycles of "7+3" or "5+2" regimens (switching between regimens was not allowed).
* Consolidation Phase (for subjects in CR/CRi after consolidation therapy) (up to four cycles of cytarabine consolidation per investigator's discretion, with midostaurin given sequentially during each cycle): Based upon the superior results reported for AML subjects less than 60 years old with normal karyotypes in prospective clinical trials and RATIFY, who achieved a CR/CRi after induction received further therapy with midostaurin. Subjects received up to four cycles of consolidation therapy. Each consolidation cycle was four weeks in duration, and was to begin within two weeks following hematologic recovery (ANC ≥ 1000/μL, platelet count ≥ 100,000/μL), but not sooner than 31 days from the beginning of the previous cycle. A bone marrow aspiration was to be performed prior to the first consolidation cycle (C1D1) and later could be performed if necessary per investigator's decision at any time during Consolidation Phase.
* Maintenance Phase (for subjects in CR/CRi after consolidation therapy): Subjects who continued in CR/CRi (by bone marrow aspiration and blood evaluation) after four cycles of consolidation therapy received midostaurin. Prior to maintenance therapy, all significant acute toxicity from consolidation therapy was to be resolved to ≤ grade 2. Subjects with CRi proceeded to maintenance therapy as per investigator's discretion and for CR subjects maintenance therapy began after hematologic recovery (ANC ≥ 1000/μL, platelet count ≥ 100,000/μL) from remission consolidation, and at least 3 days after the last dose of midostaurin during consolidation. Subjects who were unable to complete four courses of HiDAC consolidation because of toxicity could still be eligible for maintenance therapy at the discretion of the principal investigator after the last dose of consolidation after recovery from hematologic and other significant acute toxicity. A bone marrow examination was to be performed prior to the first maintenance and every 3 months during Maintenance phase. Maintenance phase was up to 12 cycles of maintenance therapy with single-agent midostaurin or until relapse, unacceptable toxicity, or death, physician's decision, subject/guardian's decision, protocol deviation, study termination by sponsor, lost to follow-up, technical problems, pregnancy, subject withdrew consent or until the end of study, whichever event occured first.

Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Combination With Standard Chemotherapy During Induction and Consolidation Followed by 12 Months of Maintenance Monotherapy in Patients With Newly-diagnosed FMS-like Tyrosine 3 (FLT3) Kinase Receptor-mutated Acute Myeloid Leukemia.

An Open-label, Multi-Center, Phase IIIb Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Patients 18 Years of Age or Older With Newly-diagnosed FLT3-mutated Acute Myeloid Leukemia Who Are Eligible for "7+3" or "5+2" Chemotherapy

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect 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

Safety of Midostaurin was represented by various types of AEs, SAEs \& death up to M24. AE: the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained. AE grades to characterize the severity of AEs were based on the Common Terminology Criteria for AEs ver. 4.03 with Grade (Gr) 1: mild; Gr 2: moderate; Gr 3: severe; Gr 4: life-threatening; Gr 5: death related to AE. AEs not related to hematological toxicities were generally of grade 1 or 2 severity. SAE: 1 of the following: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, i.e. an event that jeopardizes the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed above, requires inpatient hospitalization or prolongation of existing hospitalization with a few exceptions.

CR/CRi rate is defined as the percentage of patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per local assessment in Induction, Consolidation and Maintenance phases. CR/CRi rate was calculated based on the full analysis set (FAS).

Complete remission (CR): Bone marrow blasts \<5% with spicules; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) \>1.0 x109/L; platelet count \>100 x 109/L; independence of red cell transfusions.

CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (\<1.0 x109/L) or thrombocytopenia (\<100 x 109/L)

Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.

Induction Phase

Consolidation Phase

Maintenance Phaase

Patients from all 3 Phases (Induction, Consolidation and Maintenance).

Overall

Age, Continuous

Sex: Female, Male

White

Other

Unknown

Missing

Race/Ethnicity, Customized

All enrolled subjects set comprises all screened subjects who are not screening failures.

Study Director

Adverse events (AEs) - all grades

Grade >=3 AEs

Serious adverse events (SAEs) - all grades

AEs leading to discontinuation - all grades

Deaths

Safety Set: The safety set comprises all subjects who received at least one dose of midostaurin

Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24).

Complete remission (CR)

Complete remission with incomplete recovery (CRi)

The full analysis set (FAS) comprises all subjects who received at least one dose of midostaurin and have a documented FLT3 mutation (ITD or TKD).

Percentage of Patients With Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (CRi) as Per Local Assessment

Overall Study

Spots Global Cancer Trial Database for anthracycline ((daunorubicin or idarubicin): induction phase only