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Acute Myeloid LeukemiaPhase 1NCT01174888

Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia

A Phase 1 study testing midostaurin, Bortezomib and mitoxantrone hydrochloride in people with Acute Myeloid Leukemia and Acute Myeloid Leukemia With Multilineage Dysplasia Following, run by Alison Walker at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

RATIONALE: Bortezomib and midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
midostaurin, Bortezomib and mitoxantrone hydrochloride
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
1 siteUnited States
Study dates
Aug 2010to May 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients age >18 with relapsed or refractory acute myeloid leukemia by WHO criteria are eligible for dose levels 1 and 2. Patients age >18 and ≤ 70 with relapsed or refractory acute myeloid leukemia by WHO criteria are eligible for dose levels 3 through 6. Patients with secondary AML are eligible
  • If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
  • Eastern Cooperative Oncology Group (ECOG) performance status <2
  • Patients must have adequate organ function as defined below:
  • total bilirubin <2.0mg/dL or ≤1.5 ULN(institutional upper limit of normal)
  • AST(aspartate aminotransferase)(SGOT)/ALT(Alanine aminotransferase) (SGPT) <2.5 X institutional ULN
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  • creatinine <1.7 mg /dL
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. If the patient does not agree, the patient is not eligible. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and willingness to sign the written informed consent document
  • Patients must have recovered from the toxicity of prior therapy to less than Grade 2
  • Patients status post prior hematopoietic stem cell transplantation are eligible

Who cannot join

  • Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Hydroxyurea may be administered until initiation of treatment on the study
  • Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment
  • Patients with active central nervous system disease or with granulocytic sarcoma as sole site of disease
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to midostaurin, bortezomib, mitoxantrone, etoposide or cytarabine that are not easily managed. Patient has a hypersensitivity to bortezomib, boron, or mannitol.
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.
  • Ejection fraction <50%
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  • Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Pregnant women or women who are breastfeeding are excluded from this study.
  • Patients with pre-existing Grade 2 or higher neuropathy or other serious neurologic toxicity that would significantly increase risk of complications from bortezomib therapy are excluded.
  • Patients with a known confirmed diagnosis of HIV infection (due to concern for increased toxicity with the regimen in combination with HAART) or active viral hepatitis.
  • Patients with any pulmonary infiltrate including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray are not eligible until pulmonary infiltrates have completely resolved.
  • Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1.
  • Patients with advanced malignant solid tumors are excluded.
  • Patients with known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of midostaurin.
  • Patients with prior midostaurin treatment are excluded.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • The Ohio State University Medical Center

    Columbus, Ohio, 43210

Other trials in United States

About this study

Official title: Phase I Study of the Combination of Midostaurin, Bortezomib, and Chemotherapy in Relapsed/Refractory Acute Myeloid Leukemia

RATIONALE: Bortezomib and midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and midostaurin together with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with midostaurin with or without combination chemotherapy in treating patients with relapsed or refractory acute myeloid leukemia.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose (MTD) of bortezomib in combination with midostaurin and intensive chemotherapy in patients with relapsed/refractory acute myeloid leukemia (AML).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of midostaurin and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML.

SECONDARY OBJECTIVES:

  1. To determine the rate of complete remission (CR) of midostaurin and bortezomib in combination with intensive chemotherapy. II. To determine the overall response rate (ORR). III. To characterize the biological activity of midostaurin and bortezomib to potentially increase endogenous phosphatase activity and therefore inhibit aberrant tyrosine kinases by assessing FLT3 and KIT tyrosine kinase activity as well as SHP-1(Anti-Src Homology Phosphatase-1)phosphatase activity. IV. To correlate the biological activity of midostaurin and bortezomib to potentially increase endogenous phosphatase activity with clinical response. V. To conduct pharmacokinetic studies of midostaurin and bortezomib together and in combination with intensive chemotherapy.

VI. To determine the efficacy of midostaurin and bortezomib in combination with intensive chemotherapy at the maximum tolerated dose in patients with FLT3 or KIT tyrosine kinase mutations.

OUTLINE:

This is a dose escalation study of bortezomib. Patients are assigned to 1 of 2 treatment groups. GROUP I (Dose levels 1-2): Patients receive oral midostaurin twice daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. GROUP II (Dose levels 3-6): Patients receive mitoxantrone hydrochloride IV over 10 minutes, etoposide IV over 1 hour, and cytarabine IV over 6 hours on days 1-6. Patients also receive oral midostaurin twice daily on days 8-21 and bortezomib IV on days 8, 11, 15, and 18. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Being tested
midostaurin, Bortezomib, mitoxantrone hydrochloride, etoposide, cytarabine
Keywords
Acute Myeloid Leukemia, AML
Medical subject headings
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Congenital Abnormalities

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • midostaurinDrug

    Also called N-benzoyl-staurosporine, PKC412

    Drug midostaurin, Given orally given twice daily days 1-14

  • BortezomibDrug

    Also called LDP 341, MLN341, PS-341, VELCADE

    Bortezomib given IV on days 1, 4, 8, and 11

  • mitoxantrone hydrochlorideDrug

    Also called CL 232315, DHAD, DHAQ, dihydroxyanthracenedione

    Patients receive mitoxantrone hydrochloride IV over 10 minutes

  • etoposideDrug

    Also called Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, epipodophyllotoxin, VePesid

    Patients receive etoposide IV over 1 hour

  • cytarabineDrug

    Also called ARA-C, ARA-cell, arabinofuranosylcytosine, arabinosylcytosine

    Patients receive cytarabine IV over 6 hours on days 1-6

Study groups in NCT01174888
Study groupRoleWhat they receive
GROUP I (Dose levels 1-2):ExperimentalPatients receive midostaurin orally (PO) twice daily on days 1-14 and bortezomib intravenously (IV) on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: midostaurin; Drug: Bortezomib
GROUP II (Dose levels 3-6)ExperimentalPatients receive mitoxantrone hydrochloride IV over 10 minutes, etoposide IV over 1 hour, and cytarabine IV over 6 hours on days 1-6. Patients also receive midostaurin PO twice daily on days 8-21 and bortezomib IV on days 8, 11, 15, and 18. Treatment continues in the absence of disease progression or unacceptable toxicity.
Receives: Drug: midostaurin; Drug: Bortezomib; Drug: mitoxantrone hydrochloride; Drug: etoposide; Drug: cytarabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Determine maximum tolerated dose (MTD) of bortezomib and midostaurin in combination with MEC salvage chemotherapy

    Maximum tolerated dose of bortezomib and midostaurin in combination with MEC(mitoxantrone, etoposide,cytarabine)salvage chemotherapy. Specific toxicities and Dose-limiting toxicity of midostaurin and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML.

    Measured: up to 28 months

Secondary outcomes (6)

  1. determine the rate of complete remission (CR)

    To determine the rate of complete remission (CR) of midostaurin and bortezomib in combination with intensive chemotherapy.

    Measured: up to 28 months

  2. Determine the overall response rate (ORR)

    To determine the overall response rate (ORR)

    Measured: up to 28 months

  3. Characterize the biological activity of midostaurin and bortezomib

    Characterize the biological activity of midostaurin and bortezomib to potentially increase endogenous phosphatase activity and therefore inhibit aberrant tyrosine kinases by assessing FLT3(fetal liver kinase-2)and KIT tyrosine kinase activity as well as SHP-1 phosphatase activity.

    Measured: up to 28 months

  4. Correlate the biological activity of midostaurin and bortezomib

    To correlate the biological activity of midostaurin and bortezomib to potentially increase endogenous phosphatase activity with clinical response.

    Measured: up to 28 months

  5. Conduct pharmacokinetic studies of midostaurin and bortezomib

    To conduct pharmacokinetic studies of midostaurin and bortezomib together and in combination with intensive chemotherapy.

    Measured: up to 28 months

  6. Determine the efficacy of midostaurin and bortezomib

    To determine the efficacy of midostaurin and bortezomib in combination with intensive chemotherapy at the maximum tolerated dose in patients with FLT3 or KIT tyrosine kinase mutations.

    Measured: up to 28 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Aug 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionApr 2014
  4. Study completionMay 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
34 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01174888
Sponsor's protocol ID
OSU-09111
Other IDs
NCI-2010-01335
Status last verified
Jun 2016
First submitted
2 Aug 2010
Last updated
6 Jul 2016
Results posted
No
Data monitoring committee
Yes

Publications

  • Walker AR, Wang H, Walsh K, Bhatnagar B, Vasu S, Garzon R, Canning R, Geyer S, Wu YZ, Devine SM, Klisovic R, Blum W, Marcucci G. Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. Leuk Lymphoma. 2016 Sep;57(9):2100-8. doi: 10.3109/10428194.2015.1135435. Epub 2016 Jan 19.

    PubMed 26784138

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing midostaurin, Bortezomib and mitoxantrone hydrochloride in people with Acute Myeloid Leukemia and Acute Myeloid Leukemia With Multilineage Dysplasia Following, run by Alison Walker at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Jul 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determine maximum tolerated dose (MTD) of bortezomib and midostaurin in combination with MEC salvage chemotherapy (time frame: up to 28 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01174888, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jul 2016; AzTrials last refreshed its copy on 7 Nov 2026.

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