Selinexor and Chemotherapy in Treating Patients With Relapsed or 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

Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Official Title

Phase 1 Study of Selinexor in Combination With Topoisomerase-II Inhibition in Acute Myeloid Leukemia

Brief Summary

      This phase I trial studies the side effects and best dose of selinexor when given together
      with etoposide with or without mitoxantrone hydrochloride and cytarabine in treating patients
      with acute myeloid leukemia that has returned (relapsed) or has not responded to treatment
      (refractory). Selinexor may help stop the growth of tumor cells by blocking an enzyme needed
      for cancer cell growth. Drugs used in chemotherapy, such as etoposide, mitoxantrone
      hydrochloride, and cytarabine, work in different ways to stop the growth of cancer cells,
      either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Giving chemotherapy together with selinexor work better in treating relapsed or
      refractory acute myeloid leukemia.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of selinexor in combination with mitoxantrone
      hydrochloride, etoposide, cytarabine (MEC) or oral etoposide (respective cohorts are
      independent of each other) in patients with relapsed or refractory acute myeloid leukemia
      (AML).

      II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting
      toxicities (DLT) of these combinations.

      III. To determine the recommended phase 2 dose (RP2D) of these combinations.

      SECONDARY OBJECTIVES:

      I. To determine the rate and duration of complete remission (CR) ± hematologic recovery of
      selinexor plus MEC therapy in AML.

      II. To determine the overall response rate (ORR). III. To define the rate of complete
      remission (CR + CR with incomplete blood count recovery [CRi]) rate by the end of induction
      therapy.

      IV. Determine the disease-free survival for patients who reached CR/CRi within 1 year.

      TERTIARY OBJECTIVES:

      I. To conduct pharmacodynamic studies by measuring the effect of these chemotherapy
      combinations on the inhibition of exportin 1 (XPO1).

      II. To conduct pharmacokinetic sampling of selinexor and etoposide at limited time points to
      assess drug metabolism, peak plasma levels and area under curve (AUC).

      OUTLINE: This is a dose-escalation study of selinexor. Patients are assigned to 1 of 2
      cohorts.

      COHORT A (PATIENTS FIT FOR INTENSIVE THERAPY, AGE < 60): Patients receive mitoxantrone
      hydrochloride intravenously (IV), etoposide IV, and cytarabine IV once daily (QD) on days 1-6
      and selinexor orally (PO) on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course
      (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are
      evaluated for stem cell transplant; patients who do not proceed to transplant may receive
      selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.

      COHORT B (PATIENTS UNFIT FOR INTENSIVE THERAPY, AGE ≥ 60): Patients receive etoposide PO QD
      on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28
      days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients
      not achieving response after 4 courses discontinue treatment; patients achieving response may
      receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue
      selinexor as monotherapy at the discretion of the principal investigator.

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

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

MTD of selinexor, defined as the highest safely tolerated dose where, at most, one patient experiences DLT in 6 evaluable patients, with the next higher dose having at least 2 patients who experience DLT

Secondary Outcome

 Degree of response

Condition

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Intervention

mitoxantrone hydrochloride

Study Arms / Comparison Groups

 Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Description:  Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy 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

23

Start Date

May 18, 2015

Completion Date

March 6, 2018

Primary Completion Date

March 6, 2018

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with relapsed or refractory AML; Cohort A patients must be < 60 years of age
             and have failed at least one prior induction regimen for AML; Cohort B patients must
             be ≥ 60 years of age, unfit for intensive therapy (physician opinion), and have failed
             an induction regimen for AML. The maximum number of prior lines of induction for both
             cohorts is 3

          -  Patients with secondary AML or therapy related disease (t-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

          -  Total bilirubin < 2.0 mg/dL, except when patient is known to have Gilbert's Syndrome,
             the total bilirubin can be ≤3.0 mg/dL.

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 X institutional upper limit of normal

          -  Creatinine (Cr) clearance > 50 mL/min by Modification of Diet in Renal Disease (MDRD)
             calculation

          -  New York Heart Association (NYHA) congestive heart failure (CHF) class II or better

          -  Cardiac ejection fraction >= 50%

          -  Female patients of child-bearing potential must agree to use dual methods of
             contraception and have a negative serum pregnancy test at screening, and male patients
             must use an effective barrier method of contraception if sexually active with a female
             of child-bearing potential; acceptable methods of contraception are condoms with
             contraceptive foam, oral, implantable or injectable contraceptives, contraceptive
             patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is
             surgically sterilized or post-menopausal; for both male and female patients, effective
             methods of contraception must be used throughout the study and for three months
             following the last dose

          -  Ability to understand and willingness to sign the written informed consent document

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering 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 (CNS) malignancy; asymptomatic small
             lesions are not considered active; treated lesions may be considered inactive if they
             are stable for at least 3 months; patients with malignant cells in their cerebrospinal
             fluid (CSF) without CNS symptoms may be included

          -  Major surgery within 2 weeks before day 1

          -  Uncontrolled active infection; patients with infection requiring parenteral
             antibiotics are eligible if the infection is controlled

          -  Patients with significantly diseased or obstructed gastrointestinal tract or
             uncontrolled vomiting or diarrhea

          -  History of seizures, movement disorders or cerebrovascular accident within the past 3
             years prior to cycle 1 day 1

          -  Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased
             visual acuity

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure (New York Heart Association [NYHA) class III or IV), unstable
             angina pectoris, myocardial infarction within 6 months prior to enrollment, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities; prior to study entry, any
             electrocardiogram (ECG) abnormality at screening has to be documented by the
             investigator as not medically relevant

          -  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;
             confirmation that the subject is not pregnant must be established by a negative serum
             beta (β)-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during
             screening; pregnancy testing is not required for post-menopausal or surgically
             sterilized women

          -  Patients with advanced malignant solid tumors

          -  Patients whom, in the opinion of the investigators, are significantly below their
             ideal body weight

          -  Patients who are not able to swallow capsules or tablets
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Bhavana Bhatnagar, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02299518

Organization ID

OSU 14089

Secondary IDs

NCI-2014-02229

Responsible Party

Sponsor-Investigator

Study Sponsor

Bhavana Bhatnagar

Collaborators

 Karyopharm Therapeutics Inc

Study Sponsor

Bhavana Bhatnagar, Principal Investigator, Ohio State University Comprehensive Cancer Center


Verification Date

April 2018