Midostaurin in Treating Older Patients With Mutated Acute Myeloid Leukemia Post-Transplant

An Open-Label Extension Study of Post-Transplant Maintenance Midostaurin (PKC412) in Elderly Patients (Age ≥ 60 Years) With FLT3-ITD/TKD Mutated AML Who Previously Received Midostaurin and Decitabine as Part of Study HEMAML0022 / CPKC412AUS27T

This phase 2 trial studies the side effects and how well midostaurin works in treating older patients with acute myeloid leukemia with change in genetic material post-hematopoietic cell transplantation. Midostaruin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving midostaruin post-transplant may improve patient outcomes.

Study Overview

• Status: Withdrawn
• Conditions: Adult Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia With Gene Mutations
• Intervention / Treatment: Drug: Midostaurin

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the efficacy and safety of maintenance midostaurin (a fms related tyrosine kinase 3 [FLT3] inhibitor) for elderly patients with FLT3-internal tandem duplication (ITD)/tyrosine kinase domain (TKD) mutated acute myeloid leukemia (AML) who were previously enrolled on study HEMAML0022/CPKC412AUS27T and have then undergone allogeneic transplant.

SECONDARY OBJECTIVES:

I. To determine whether maintenance midostaurin after allogeneic transplant decreases the relapse rate in patients with FLT3-ITD/TKD mutated AML.

OUTLINE:

Beginning 30 days post-hematopoietic cell transplantation (HCT), patients receive midostaurin orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then up to 1 year.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA

• Elderly patients with FLT3-mutated acute myeloid leukemia (AML)
• Prior enrollment in Stanford study IRB-25737
• In continued complete remission
• ≥ 30 days but ≤ 90 days post allogeneic hematopoietic cell transplant (HCT); treatment on this study protocol must begin before day 90 post-HCT
• Absolute neutrophil count (ANC) ≥ 1000 cells/uL
• Hemoglobin ≥ 8.0 g/dL and not requiring regular transfusions
• Platelets ≥ 50,000 cells/uL and not requiring regular transfusions
• Aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN)
• Alanine aminotransferase (ALT) ≤ 2.5 X ULN
• Serum bilirubin ≤ 2.5 times ULN
• Ability to give written informed consent, including via legally authorized representative
• Corrected QT (QTc) ≤ 450 msec
• Ejection fraction (EF) ≥ 45% by 2-dimensional transthoracic echocardiography (TTE) or multiple-gated acquisition (MUGA)
• Sexually active males, including vasectomized males, must agree via informed consent to use a condom during vaginal, anal, or oral intercourse, while taking midostaurin and for 5 months after stopping midostaurin

• Females must have or be:

  • Negative pregnancy test, within 21 days of the first dose of midostaurin OR

  • Not of childbearing potential as follows:

    • Has undergone a hysterectomy or bilateral oophorectomy;
    • Has not had menses at any time in the preceding 24 consecutive months

EXCLUSION CRITERIA

• Uncontrolled acute graft-vs-host disease (GVHD) grade 3 to 4
• Uncontrolled active infection
• Evidence of active AML (eg, circulating peripheral blasts on complete blood count)
• Known confirmed diagnosis of human immunodeficiency virus (HIV) infection
• Known confirmed diagnosis of active viral hepatitis
• QTc > 450 msec
• Congenital long QT syndrome
• History of presence of sustained ventricular tachycardia, history of ventricular fibrillation or torsades de pointes
• Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm)
• Bifascicular block (right bundle branch block plus left anterior hemiblock)
• Congestive heart failure (CHF) New York Heart Association (NYHA) class 3 or 4
• Cardiac ejection fraction (EF) < 45% within 28 days prior to starting cycle 1
• Other known malignancy (except carcinoma in situ)

• Other concurrent severe and/or uncontrolled medical condition which could compromise participation in the study, eg:

  • Uncontrolled diabetes
  • Chronic active pancreatitis
  • Myocardial infarction within 6 months
  • Poorly-controlled hypertension
  • Chronic kidney disease
• Received any investigational agent within 30 days prior to day 1
• Antineoplastic chemotherapy or radiotherapy within 28 days prior to cycle 1
• No plans for concurrent chemotherapy while on study (exception: antineoplastic drugs used as part of GVHD prophylaxis or treatment)
• Any surgical procedure, excluding central venous catheter placement, bone marrow biopsy or other minor procedures (eg, skin biopsy) within 14 days of day 1
• Unwillingness or inability to comply with the protocol
• Known malignant disease of the central nervous system
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to midostaurin
• Concomitant use of strong inhibitors of cytochrome P450 family 3 subfamily A member 4 (CYP3A4)
• Pregnant or lactating
• Women of child-bearing potential

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midostaurin; Beginning 30 days post-HCT, participants receive oral midostaurin twice-a-day in 28-day treatment cycles, continuing up to 12 cycles in the absence of disease progression or unacceptable toxicity.	Drug: Midostaurin; Given PO; Other Names: Rydapt; CGP 41251; PKC-412; N-benzoyl-staurosporine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival		Up to 1 year
Incidence of adverse events using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0		Up to 30 days
Overall survival	Calculated and reported with Kaplan Meier curves. The statistical analyses will focus on estimation rather than hypothesis testing. Two-sided 95% confidence intervals will be presented, using the Clopper-Pearson method for proportions and using Greenwood's formula for time to event outcomes.	Up to 1 year
Relapse free survival	Calculated and reported with Kaplan Meier curves. The statistical analyses will focus on estimation rather than hypothesis testing. Two-sided 95% confidence intervals will be presented, using the Clopper-Pearson method for proportions and using Greenwood's formula for time to event outcomes.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse rate after allogeneic transplant	Described using proportions.	Up to 1 year

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: David Iberri, MD, Stanford University

Study record dates

Study Major Dates

• Primary Completion (Actual): April 1, 2018
• Study Completion (Actual): April 1, 2018

Study Registration Dates

• First Submitted: March 25, 2016
• First Submitted That Met QC Criteria: March 25, 2016
• First Posted (Estimate): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): May 4, 2018
• Last Update Submitted That Met QC Criteria: May 1, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Midostaurin; Staurosporine
• Other Study ID Numbers: IRB-31582; NCI-2016-00424 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); HEMAML0022-EXT (Other Identifier: OnCore); NCT02723435 (Other Identifier: Stanford University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No