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

• ClinicalTrials.gov Identifier: NCT03379727
• Recruitment Status: Completed
• First Posted: December 20, 2017
• Last Update Posted: February 15, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: December 14, 2017
• First Posted Date: December 20, 2017
• Last Update Posted Date: February 15, 2022
• Actual Study Start Date: February 13, 2018
• Actual Primary Completion Date: July 9, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2017)

Percentage of patients with AEs, Grade 3&4 AEs, SAEs, AEs leading to discontinuation, and deaths up to 24 months. [ Time Frame: Baseline up to approximatly 24 months ]

To further assess the safety of midostaurin in induction, consolidation and maintenance therapy, including, the "7+3" regimen, higher dose of Daunorubicin (60-90mg/m2/day), the substitution of Daunorubicin by Idarubicin and lower dose of Cytarabine (100-200 mg/m2/day) and also allowing the "5+2" reduced dose regimen.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 19, 2017)

Percentage of patients with CR/CRi as per local assessment [ Time Frame: Baseline up to approximately 24 months ]

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 phase. CR/CRi rate will be calculated based on the full analysis set (FAS).

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: December 19, 2017)

Health Care Resource Utilization during maintenance [ Time Frame: During maintenance up to 12 months ]

Collection of health care resource utilization (HCRU) data will focus on hospitalization: reason for the hospitalization, number of hospital days by ward type (e.g. hospital unit, emergency room, intensive care unit), discharge status, and the names of concomitant medications during hospital stay. These measures will be used to quantify the number of hospital day's impact of therapy during the maintenance phase and derive components of the economic impact of midostaurin during maintenance.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Combination With Standard Chemotherapy During Induction and Consolidation Followed by 12 Months of Monotherapy in Patients With Newly-diagnosed FLT3-mutated Acute Myeloid Leukemia.
• Official Title: 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
• Brief Summary: The purpose of this study is 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 are eligible for standard induction and consolidation
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Considering the limited safety impact and the significant clinical benefit of the addition of midostaurin to the standard "7+3" regimen in the RATIFY study (CPKC412A2301), this Phase IIIb study is designed as a single arm study and allows 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 is the primary endpoint. CR/CRi (see Section 7.2.1) in induction, consolidation and maintenance therapy is collected as secondary endpoint.

Patients who are newly diagnosed with AML, have a known FLT3 ITD or TKD, mutation and have recently started on "7+3" or "5+2" in induction and high dose of cytarabine in consolidation will be consented and screened for the clinical study.

Number of Arms:

1

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Acute Myeloid Leukemia

Intervention

Drug: Midostaurin

Orally administered inhibitor of multiple tyrosine kinases

Study Arms

Experimental: Midostaurin

Induction phase - D8 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

Intervention: Drug: Midostaurin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 9, 2021): 303
• Original Estimated Enrollment (submitted: December 19, 2017): 300
• Actual Study Completion Date: July 9, 2021
• Actual Primary Completion Date: July 9, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Written informed consent must be obtained prior to any screening procedures.
2. Patients must be 18 years of age or older at the time of signing informed consent.
3. Patients must have a documented unequivocal diagnosis of AML according to WHO 2008 classification. A bone marrow or blood blast count of ≥ 20% is required, except for AML with t(15;17), t(8;21), inv(16) or t(16;16) where blast count may be <20%, and, excluding M3 (acute promyelocytic leukemia).
4. Patients with secondary AML are eligible, e.g. patients with antecedent history of treatment for prior malignancy. AML patients with a history of antecedent treatment for myelodysplasia (MDS), e.g. azacitidine or decitabine, remain eligible for treatment on this study. These agents must have been discontinued for a period of at least 30 days or 5 half-lives of the drug (whichever is greater) before midostaurin can be administered.
5. Patients must have started "7+3" or "5+2" first induction chemotherapy regimen.
6. Patients must have a documented FLT3 mutation (ITD or TKD).).
7. Patients must have an ECOG Performance Status of ≤ 2
8. Patients requiring intrathecal chemotherapy must have a minimum washout of 48 hours prior to the first dose of midostaurin
9. Patients must have Total Bilirubin ≤ 2.5 x ULN
10. Patients must have Serum Creatinine ≤ 2.5 x ULN
11. Patients must be able to communicate well with the investigator to understand and comply with the requirements of the study
12. Women of child-bearing potential must have a negative pregnancy test before starting use of midostaurin.

Exclusion criteria:

Patients eligible for this study must not meet any of the following criteria:

1. Prior therapy for AML with the following exceptions:

   1. emergency leukapheresis
   2. emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days
   3. cranial RT for CNS leukostasis (one dose only)
   4. growth factor/cytokine support
2. Patients with LVEF less than 45% (by echocardiogram or MUGA) or symptomatic congestive heart failure (Class III or IV) according to New York Heart Association (NYHA) classification
3. Patients with any pulmonary infiltrate including those suspected to be of infectious origin (unless resolved to ≤ Grade 1 within screening timeframe)
4. Patients with any uncontrolled illness, including, but not limited to, acute or chronic pancreatitis or uncontrolled infection
5. QTc >470 msec on screening ECG.
6. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment.
7. Participation in a prior investigational interventional (drug) study with administration of the investigational product within 30 days or 5 half-lives of the investigational product, whichever is longer.

8. Pregnancy statements and contraception requirements:

   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 4 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 6 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 or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

   In case of use of oral contraception women should also add a barrier method of contraception, particularly as it is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives.

   Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment to avoid conception or embryo-fetal harm.

9. Patients enrolled in this study are not permitted to participate in additional parallel study drug or device studies.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Croatia, Czechia, Estonia, Finland, France, Hungary, Italy, Lithuania, Norway, Romania, Serbia, Slovakia, Spain, Sweden
• Removed Location Countries: Greece

Administrative Information

• NCT Number: NCT03379727
• Other Study ID Numbers: CPKC412A2408; 2016-004440-12 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: February 2022