Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia

NCT01093573 | Completed Phase 1 Results DMC

• 2 other identifiers: CASE1908NCI-2009-01285
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 2

Brief Summary

RATIONALE: Midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Midostaurin may help azacitidine kill more cancer cells by making the cancer cells more sensitive to the drug. PURPOSE: This phase I/II trial is studying the side effects and best dose of midostaurin when given together with azacitidine and to see how well it works in treating elderly patients with acute myelogenous leukemia.

Conditions

Untreated Adult Acute Myeloid Leukemia

Keywords

Untreated myelodysplastic syndromes

Outcome Measures

Primary Outcomes (4)

• Maximum Tolerated Dose of Midostaurin in Combination With Azacitidine in Patients With Acute Myelogenous Leukemia (Phase I)

  Patients received azacitidine 75 mg/m intravenous over 30 minutes daily for 7 consecutive days followed by escalating doses of oral midostaurin (25 mg bid, 50 mg bid, and 75 mg bid) days 8-21. Determination of the maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLT) observed during the first cycle of treatment

  Day 28

• Number of Participants With Hematologic Improvement (Phase I)

  Number of participants with HI. Hematologic improvement (HI): must last at least 2 months in the absence of ongoing cytotoxic therapy and will be another endpoint of interest (although it will not be considered in the final statistical analysis) and will be defined according to IWG criteria .

  After 2 cycles of therapy

• Overall Response Rate (Phase II)

  Number of participants with CR, CRi, PR and Hematologic improvement (HI). Response will be assessed using the standard morphologic criteria for acute leukemia as follows: Complete remission (CR): ANC ≥ 1000/ uL and platelets of \> 100,000/ uL without circulating blasts and bone marrow with \< 5% blasts and no Auer rods; Morphologic complete remission with incomplete blood recovery (CRi): Patients fulfills all of the criteria for remission except for residual neutropenia (ANC \< 1000/ uL) or thrombocytopenia (platelet count \< 100,000/uL). Partial remission (PR): This designation requires at least a 50% decrease in the bone marrow blasts to 5-25%.

  after 4 months of treatment

• Toxicity Profile (Phase II)

  Number of patients experiencing at least one instance of specific treatment emergent adverse events

  during treatment up to 10 cycles

Secondary Outcomes (3)

• Duration of Response

  Up to 3 years

• Overall Survival (Phase II)

  Up to 3 years

• Correlate Treatment Response With FLT3 Mutational Status in a Descriptive Fashion.(Phase I)

  Baseline to 4 cycles (16 weeks)

Other Outcomes (2)

• Pharmacokinetic Profile of Midostaurin Given With Azacitidine (Phase I)

  after 2 cycles

• Changes of Phosphorylation Status of FLT3 in Blood and Bone Marrow Samples (Phase I/II)

  Baseline to 4 cycles (16 weeks)

Study Arms (3)

Dose Level 1

EXPERIMENTAL

Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21

Drug: midostaurin; Drug: azacitidine; Other: bone marrow aspiration; Other: mutation analysis; Other: Pharmacokinetic study

Dose Level 2

EXPERIMENTAL

Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21

Drug: midostaurin; Drug: azacitidine; Other: bone marrow aspiration; Other: mutation analysis; Other: Pharmacokinetic study

Dose Level 3

EXPERIMENTAL

Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21

Drug: midostaurin; Drug: azacitidine; Other: bone marrow aspiration; Other: mutation analysis; Other: Pharmacokinetic study

Interventions

midostaurin DRUG

Given orally

Also known as: N-benzoyl-staurosporine, PKC412

Dose Level 1; Dose Level 2; Dose Level 3

azacitidine DRUG

Given IV

Also known as: 5-AC, 5-azacytidine, 5-AZC, azacytidine, ladakamycin, Vidaza

Dose Level 1; Dose Level 2; Dose Level 3

bone marrow aspiration OTHER

Correlative study: Pretreatment bone marrow aspirates or blood \[(3 ml in EDTA tube (purple top)\] will be analyzed according to local institution guidelines to determine whether blasts contain wild type Flt3, ITD, or Flt 3 mutations.

Dose Level 1; Dose Level 2; Dose Level 3

mutation analysis OTHER

Correlative study

Dose Level 1; Dose Level 2; Dose Level 3

Pharmacokinetic study OTHER

Correlative study: Concentrations of unchanged midostaurin and its major metabolites, CGP52421 and CGP62221 in plasma samples will be determined using a validated liquid chromatography / mass spectrometry method.

Also known as: Pharmacokinetic studies

Dose Level 1; Dose Level 2; Dose Level 3

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologic proof of active AML at time of enrollment
• Phase I and II portion: Subjects of any age with untreated AML, if not candidates for standard induction chemotherapy or with poor risk AML (i.e. preceding MDS, myeloproliferative syndromes, leukemia due to cytotoxic chemotherapy for another condition, adverse cytogenetics or complex karyotype), or any subjects \> 70 years of age with untreated AML. Acute promyelocytic leukemia (FAB M3) is excluded
• Please note: prior intensive induction therapy for acute leukemia is allowed only in the phase I portion of this study
• PHASE I PORTION ONLY: Patients of any age who have received no more than one prior attempt at induction chemotherapy (and may have received treatment consolidation), must have recovered from acute toxicities of therapy and be \>= 4 weeks from last dose of cytotoxic treatment; patients who have received prior autologous or allogeneic stem cell transplantation are not eligible; patients may have received 1 or 2 cycles of cytarabine-based therapy as attempted induction.
• Phase II portion: Patients must have not received any prior intensive induction therapy for AML.
• Intensive induction includes standard induction chemotherapy such as 7 \& 3, high dose cytarabine, mitoxantrone-etoposide, low-dose subcutaneous cytarabine.
• Allowed "non-intensive" prior treatments for pre-existing hematologic conditions (i.e., MDS, chronic myelomonocytic leukemia \[CMML\]) will include: hydroxyurea, thalidomide, hematopoietic growth factors, Zarnestra, Lenalidomide, arsenic, Imatinib, and corticosteroids, suberoylanilide hydroxamic acid \[SAHA\] inhibitors; hydroxyurea is allowed up to 24 hours before initiating treatment and to control blood counts during the first cycle of chemotherapy after azacitidine has completed; a minimum of 4 weeks must have elapsed since the administration of thalidomide, Zarnestra, Revlimid, arsenic, SAHA inhibitors, or any investigational medication; a minimum of five days must have elapsed since the administration of growth factors
• Prior cytotoxic chemotherapy for another condition treated with curative intent is allowed provided at least 18 months has elapsed between last treatment and enrollment on protocol
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 1.5 times the upper limits of normal
• Serum bilirubin =\< 1.5x upper limit of normal
• Creatinine =\< 1.5x upper limit of normal
• Life expectancy without treatment of at least 12 weeks
• Patients with and without FLT3 mutations will be eligible to participate
• Patients must have the ability and willingness to sign a written informed consent document

You may not qualify if:

• Acute promyelocytic leukemia (FAB M3)
• Prior autologous or allogeneic stem cell transplant
• Prior azacitidine, decitabine, or midostaurin
• Patients with known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of midostaurin; patients with gastric bypass surgery are excluded
• Patients with any other known active cancer (except carcinoma in-situ), concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, pulmonary, chronic renal disease, active uncontrolled infection)
• Cardiovascular Criteria will exclude a patient from participation in the study will include:
• Screening electrocardiogram (ECG) with a QTc \> 450 msec;
• Patients with congenital long QT syndrome;
• History or presence of sustained ventricular tachycardia;
• Any history of ventricular fibrillation or torsades de pointes;
• Bradycardia defined as heart rate (HR) \< 50 bpm;
• Right bundle branch block + left anterior hemiblock (bifascicular block);
• Patients with myocardial infarction or unstable angina \< 6 months prior to starting study drug;
• Congestive heart failure (CHF) New York (NY) Heart Association class III or IV;
• Patients with an ejection fraction =\< 45% assessed by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) scan within 14 days of day 1

Sponsors & Collaborators

• Brenda Cooper, MD: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

Related Publications (1)

• Tomlinson BK, Gallogly MM, Kane DM, Metheny L, Lazarus HM, William BM, Craig MD, Levis MJ, Cooper BW. A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia. Clin Lymphoma Myeloma Leuk. 2020 Apr;20(4):226-233.e1. doi: 10.1016/j.clml.2019.10.018. Epub 2019 Nov 6.

  PMID: 32085993 BACKGROUND

MeSH Terms

Interventions

midostaurin; Azacitidine

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Brenda Cooper MD
• Organization: Case Comprehensive Cancer Center

Brenda.cooper@uhhospitals.org

(216) 844-3213

Study Officials

• Brenda Cooper, MD

  Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 24, 2010
• First Posted: March 26, 2010
• Study Start: July 1, 2009
• Primary Completion: September 8, 2016
• Study Completion: May 5, 2017
• Last Updated: June 30, 2022
• Results First Posted: May 1, 2020

Record last verified: 2022-06

Locations

US (2)