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

Related Clinical Trial
Total Marrow Irradiation for Refractory Acute Leukemia Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia Therapeutic Allogeneic Lymphocytes and Aldesleukin in Treating Patients With High-Risk or Recurrent Myeloid Leukemia After Undergoing Donor Stem Cell Transplant MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Symptom-Adapted Physical Activity Intervention in Minimizing Physical Function Decline in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy A Phase II Study Of The Farnesyltransferase Inhibitor ZANESTRA (R115777, NSC #702818, IND #58,359) In Complete Remission Following Induction And/Or Consolidation Chemotherapy In Adults With Poor-Risk Acute Myelogenous Leukemia (AML) And High-Risk Myelodysplasia (MDS) Radiolabeled BC8 Antibody, Busulfan, Cyclophosphamide Followed by Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia in First Remission 3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia Vaccine Therapy and Basiliximab in Treating Patients With Acute Myeloid Leukemia in Complete Remission Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia PXD101 in Treating Patients With Acute Myeloid Leukemia Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Rasburicase and Allopurinol in Treating Patients With Hematologic Malignancies Lenalidomide and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Bendamustine and Idarubicin in Treating Older Patients With Previously Untreated AML or MDS Clofarabine and Cytarabine in Treating Patients With Acute Myeloid Leukemia With Minimal Residual Disease Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Decitabine, Donor Natural Killer Cells, and Aldesleukin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome SJG-136 in Treating Patients With Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndromes, Blastic Phase Chronic Myelogenous Leukemia, or Chronic Lymphocytic Leukemia Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia GTI-2040 and High-Dose Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia Connect® MDS/AML Disease Registry Combined PD1 Inhibitor and Decitabine in Elderly Patients With Relapse and Refractory Acute Myeloid Leukemia Vorinostat in Treating Patients With Acute Myeloid Leukemia Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Bortezomib in Treating Patients With High-Risk Acute Myeloid Leukemia in Remission Clofarabine, Cytarabine, and Filgrastim Followed by Infusion of Non-HLA Matched Ex Vivo Expanded Cord Blood Progenitors in Treating Patients With Acute Myeloid Leukemia Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia Economic Analysis of Blood Product Transfusions According to the Treatment of Acute Myeloid Leukaemia in the Elderly Comparison of Diagnostic Yield Among M-FISH, FISH Probe Panel and Conventional Cytogenetic Analysis in AML Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia Bortezomib in Treating Young Patients With Refractory or Recurrent Leukemia Red Cell Transfusion Goals in Patients With Acute Leukemias A PALG Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in AML Patients ≤ 60 Years Old An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia Fludarabine and Cytarabine as Continuous Infusion Plus G-CSF Priming for Elderly Patients With Resistant AML Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible Prognostic Values of Next Generation Sequencing (NGS) in Acute Myeloid Leukemia Patients With Allo-HSCT PET/MRI, 18F-FDG PET/CT and Whole Body MRI in Finding Extramedullary Myeloid Leukemia in Patients With Newly Diagnosed Acute Myeloid Leukemia Pilot Clinical Trial of Pazopanib in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or at Initial Diagnosis When no Intensive Treatment is Possible A Safety Study of SGN-CD33A in AML Patients FLAG+Ida With G-CSF Priming for Patients Younger Than 60 Years With Resistant AML Study on Number and Outcome of Pregnancy in Acute Promielocitic Leukaemia (APL) Patients Treated With Chemotherapy Biomarkers in Bone Marrow Samples From Patients With Acute Promyelocytic Leukemia Treatment Study for Children and Adolescents With Acute Promyelocitic Leukemia A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia ASCT for Relapsed APL After Molecular Remission Diagnostic Study of Patients With Acute Lymphoblastic Leukemia or Acute Promyelocytic Leukemia National Acute Promyelocytic Leukemia (APL) Observational Study NAPOLEON-Registry of the German AML Intergroup All-trans Retinoic Acid, and Arsenic +/- Idarubicin Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia AIDA 2000 Guidelines Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia The Acute Promyelocytic Leukaemia Asian Consortium (APL-AC) Project Combined Retinoic Acid,Arsenic Trioxide and Chemo for Newly-diagnosed APL French Registry of First-line Treatment of Acute Promyelocytic Leukemia New Retinoid Agent Combined With Arsenic Trioxide for Untreated Acute Promyelocytic Leukemia Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO) Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005) Long-Term Quality of Life in Patients With Acute Promyelocytic Leukemia Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia Long-term QoL in Acute Promyelocytic Leukemia Treated With ATO or Standard Chemotherapy Treatment of Non-high-risk Acute Promyelocytic Leukemia (APL) With Realgar-Indigo Naturalis Formula (RIF) Treatment of Acute Promyelocytic Leukemia With All-Trans Retinoic Acid (ATRA) and Idarubicin (AIDA) Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic Study of NRX 195183 Therapy for Patients With Relapsed or Refractory Acute Promyelocytic Leukemia Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia Proteasome Inhibition in Acute Promyelocytic Leukemia

Brief Title

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

Official Title

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

Brief 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 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.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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:

      I. 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 determine the rate of complete remission (CR)

Condition

Acute Myeloid Leukemia

Intervention

midostaurin

Study Arms / Comparison Groups

 GROUP I (Dose levels 1-2):
Description:  Patients 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

34

Start Date

August 2010

Completion Date

May 2016

Primary Completion Date

April 2014

Eligibility Criteria

        Inclusion Criteria

          -  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

               -  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

        Exclusion criteria

          -  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%

          -  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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alison Walker, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01174888

Organization ID

OSU-09111

Secondary IDs

NCI-2010-01335

Responsible Party

Sponsor-Investigator

Study Sponsor

Alison Walker

Collaborators

 Novartis

Study Sponsor

Alison Walker, MD, Principal Investigator, The Ohio State University James Cancer Hospital


Verification Date

June 2016