Clinical Trials /

Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) + Sorafenib in Acute Myeloid Leukemia

NCT02530476

Description:

There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerated dose of the combination of selinexor (KPT-330) and sorafenib (Nexavar) that can be given to patients with FLT3-ITD and -D835 mutated acute myeloid leukemia (AML) or FLT3-mutated high-risk myelodysplastic syndrome (MDS). The goal of Part 2 of this study is to learn if the dose found in Part 1 can help to control the disease. The safety of the drug combination will also be studied in both parts of this study. This is an investigational study. Sorafenib is FDA approved and commercially available to treat hepatocellular cancer. Selinexor is not FDA approved or commercially available. It is currently being used for research purposes only. The combination of selinexor and sorafenib to treat FLT3-mutated AML and high-risk MDS is investigational. The study doctor can explain how the study drugs are designed to work. Up to 52 participants will take part in this study. All will be enrolled at MD Anderson.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) + Sorafenib in Acute Myeloid Leukemia
  • Official Title: Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) + Sorafenib in Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 2014-0975
  • SECONDARY ID: NCI-2015-01523
  • SECONDARY ID: P50CA100632
  • NCT ID: NCT02530476

Conditions

  • Leukemia
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
SelinexorKPT-330Selinexor + Sorafenib
SorafenibNexavar, BAY 43-9006Selinexor + Sorafenib

Purpose

There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerated dose of the combination of selinexor (KPT-330) and sorafenib (Nexavar) that can be given to patients with FLT3-ITD and -D835 mutated acute myeloid leukemia (AML) or FLT3-mutated high-risk myelodysplastic syndrome (MDS). The goal of Part 2 of this study is to learn if the dose found in Part 1 can help to control the disease. The safety of the drug combination will also be studied in both parts of this study. This is an investigational study. Sorafenib is FDA approved and commercially available to treat hepatocellular cancer. Selinexor is not FDA approved or commercially available. It is currently being used for research purposes only. The combination of selinexor and sorafenib to treat FLT3-mutated AML and high-risk MDS is investigational. The study doctor can explain how the study drugs are designed to work. Up to 52 participants will take part in this study. All will be enrolled at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be assigned to a study
      group based on when you join this study. Up to 3 groups of up to 6 participants will be
      enrolled in Part 1 of the study, and up to 40 participants will be enrolled in Part 2.

      If you are enrolled in Part 1, the dose of selinexor and sorafenib you receive will depend on
      when you joined this study. The first group of participants will receive the starting dose
      combination level. If no intolerable side effects were seen, the next group will receive a
      higher dose of selinexor and sorafenib than Group 1. If intolerable side effects are seen,
      the next group may receive a lower dose level of selinexor and/or sorafenib. This will
      continue until the highest tolerable combination dose is found.

      If you are enrolled in Part 2, you will receive selinexor and sorafenib at the highest
      tolerable combination dose or most effective combination dose found in Part 1.

      Study Drug Administration:

      Each study cycle is 28 days. However, the study cycles may be 3-12 weeks long, depending on
      if/how the disease responds to the treatment, how your bone marrow reacts to treatment, and
      what the doctor thinks is in your best interest.

      You will take selinexor tablets by mouth 2 times each week (Monday/Wednesday or
      Tuesday/Thursday or Wednesday/Friday) for 3 weeks. You must take your dose of selinexor
      within 30 minutes after eating, with at least 4 ounces of fluids (either water, milk, juice,
      and so on). You must swallow the tablets whole. Do not crush them. If the powder comes into
      contact with your skin, you may have an increased chance of skin-related side effects.

      You will take sorafenib by mouth 2 times a day, every day. Depending on how the disease
      responds to the study drugs, the number of days you receive the study drug may change. Your
      doctor will discuss this with you. You must take your dose of sorafenib at least 1 hour
      before or 1 hour after eating.

      You will be given a drug diary and asked to write down what time you take the study drugs
      every day. You must bring in the study drug diary and any unused study drugs and bottles to
      each study visit.

      Study Visits:

      On Day 1 of Cycles 1-4 and then every 1-3 cycles after that:

        -  You will have a physical exam.

        -  You will have an EKG.

      The study doctor will tell you how often you will have these tests after Cycle 4.

      One time each week during Cycles 1-3, blood (about 1 tablespoon) will be drawn for routine
      tests. After Cycle 3, you will have this blood draw 1 time every 2-4 weeks. If the doctor
      thinks it is needed, blood may need to be drawn more often or more than 1 tablespoon of blood
      may need to be drawn.

      After Cycle 1, you may be able to have these blood draws performed at a local lab or clinic
      that is closer to your home. The results of the testing will be sent to MD Anderson for
      review. The study doctor or study staff will discuss this option with you.

      On Day 28 of Cycles 1 and 3 (+/- 7 days) and then every 1-3 cycles after that, you will have
      a bone marrow aspiration and/or biopsy to check the status of the disease.

      Every 3 months (+/- 14 days), if you can become pregnant, blood (about 1-2 tablespoons) or
      urine will be collected for a pregnancy test.

      If you stay on study for more than 6 months and you are not having side effects, you may have
      some of the above tests more or less often. The study doctor will discuss this with you.

      Length of Study:

      You may continue taking the study drugs for as long as the study doctor thinks it is in your
      best interest. You will no longer be able to take the study drugs if the disease gets worse,
      if intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      End-of-Study Visit:

      If you stop taking the study drugs before the end of Cycle 24:

        -  You will have a physical exam.

        -  Blood (about 2-3 tablespoons) will be drawn for routine tests.

        -  If the doctor thinks it is needed, you will have a bone marrow aspirate to check the
           status of the disease.

      Follow-Up:

      About 30 days (+/- 7) after your last dose of study drugs, you will have a physical exam. You
      may have this exam at MD Anderson or a local clinic near your home. If you have this exam at
      a local clinic, the results of the exam will be sent to MD Anderson for review.

      If you cannot come to MD Anderson or a local clinic, you will be called by a member of the
      study staff and asked if you have had any side effects and/or started any new treatment(s).
      This call should last about 5 minutes.

      Long-Term Follow-Up:

      If the disease appears to get better and you are responding well to the study drug, you will
      return to MD Anderson every 3-6 months for up to 5 years after your last dose of study drugs
      for the study staff to check how you are doing.

      If you cannot return to MD Anderson for these visits, you may be called by a member of the
      study staff. The call should last about 10 minutes.
    

Trial Arms

NameTypeDescriptionInterventions
Selinexor + SorafenibExperimentalCohort includes those with FLT3-ITD and -D835 mutated participants with relapsed/refractory AML, including participants who may have been previously exposed to one or more FLT3-inhibitors. Phase I Starting Dose of Sorafenib: 400 mg by mouth twice daily for a 28 day cycle. Phase I Starting Dose of Selinexor: 80 mg by mouth twice weekly for a 28 day cycle.
  • Selinexor
  • Sorafenib
Cohort 1 (FLT3-ITD inhibitor failure cohort)ExperimentalCohort includes those with FLT3-ITD and -D835 mutated relapsed/refractory AML who have failed therapy with up to two prior salvage regimens. Phase II Starting Dose of Sorafenib: Maximum tolerated dose combination from Phase I. Phase II Starting Dose of Selinexor: Maximum tolerated dose from Phase I.
  • Selinexor
  • Sorafenib
Cohort 2 (FLT3-ITD inhibitor naive cohort)ExperimentalCohort includes those with FLT3-ITD and -D835 mutated relapsed/refractory AML who have failed therapy with up to two prior salvage regimens. Phase II Starting Dose of Sorafenib: Maximum tolerated dose combination from Phase I. Phase II Starting Dose of Selinexor: Maximum tolerated dose from Phase I.
  • Selinexor
  • Sorafenib

Eligibility Criteria

        Inclusion Criteria:

          1. FLT3-ITD and/or FLT3-D835 mutated patients 18 years of age or older with relapsed/
             refractory AML (any number of relapses) including patients who may have been
             previously exposed to one or more FLT3-inhibitor therapies will be eligible for the
             phase I portion of this study.

          2. Phase II FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory patients: Patients
             should have a diagnosis of AML (de novo or transformed from hematologic malignancies).
             Patients with high-risk myelodysplastic syndrome (MDS) (defined as having >/= 10%
             blasts in the bone marrow) or patients with Chronic Myelomonocytic Leukemia (CMML)
             (having >/= 10% blasts in the bone marrow) may also be eligible after discussion with
             Principal Investigator (PI). The patients should have one of the following features:
             1. Patients with AML should have failed any prior induction therapy or have relapsed
             after prior therapy. 2. Patients with high-risk MDS or high-risk CMML should have
             failed any prior therapy for the MDS or CMML. 3. Patients with MDS or CMML who
             received therapy for the MDS or CMML and progress to AML are eligible at the time of
             diagnosis of AML regardless any prior therapy for AML. The WHO classification will be
             used for AML.

          3. Patients must be eligible for one of two cohorts: Cohort 1 (FLT3 and/or FLT3-D835
             inhibitor failure cohort) in FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory AML
             who have failed therapy with up to two prior salvage regimens (SCT or stem cell
             therapy for patients who previously underwent SCT/stem cell therapy in remission will
             not be considered a salvage regimen) and have previously been exposed at least one
             prior FLT3 inhibitor. Cohort 2 (FLT3 inhibitor naive cohort) in FLT3-ITD and/or
             FLT3-D835 mutated relapsed/refractory who have failed therapy with up to two prior
             salvage regimens (SCT or stem cell therapy for patients who previously underwent
             SCT/stem cell therapy in remission will not be considered a salvage regimen) with no
             prior exposure to any FLT3 inhibitor.

          4. Age >/=18 years

          5. ECOG Performance Status </=2

          6. Patients should have estimated life expectancy of >3 months at study entry

          7. Adequate hepatic (serum total bilirubin </= 2.0 x upper limit normal (ULN) (or </= 3.0
             x ULN if deemed to be elevated due to leukemia), alanine aminotransferase and/or
             aspartate transaminase </= 3.0 x ULN (or </= 5.0 x ULN if deemed to be elevated due to
             leukemia), and renal function (creatinine </= 2.0 mg/dL).

          8. Patients must provide written informed consent.

          9. In the absence of rapidly progressing disease, the interval from prior treatment to
             time of initiation of selinexor and sorafenib administration will be at least 2 weeks
             for cytotoxic agents or at least 5 half-lives for cytotoxic/noncytotoxic agents. The
             use of chemotherapeutic or anti-leukemic agents is not permitted during the study with
             the following exceptions: (1) intrathecal (IT) therapy for patients with controlled
             CNS leukemia at the discretion of the PI and with the agreement of the Sponsor.
             Controlled CNS leukemia is defined by the absence of active clinical signs of CNS
             disease and no evidence of CNS leukemia on the most recent 2 simultaneous CSF
             evaluations. (2) Use of one dose of cytarabine (up to 2 g/m2) or hydroxyurea for
             patients with rapidly proliferative disease is allowed before the start of study
             therapy and for the first four weeks on therapy. These medications will be recorded in
             the case-report form.

         10. Baseline ejection fraction must be >/= 40%.

         11. Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
             at least 12 months) or if of childbearing potential, must have a negative serum or
             urine pregnancy test within 72 hours before the start of the treatment.

         12. Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 3 months after the last treatment. Males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 3 months after the last treatment. Adequate methods of contraception
             include: Total abstinence when this is in line with the preferred and usual lifestyle
             of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
             post-ovulation methods) and withdrawal are not acceptable methods of contraception.
             Female sterilization (have had surgical bilateral oophorectomy with or without
             hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
             case of oophorectomy alone, only when the reproductive status of the woman has been
             confirmed by follow up hormone level assessment

         13. (Continued from Criteria 12) Male sterilization (at least 6 months prior to
             screening). For female patients on the study, the vasectomized male partner should be
             the sole partner for that patient Combination of any of the two following (a+b or a+c
             or b+c) Use of oral, injected or implanted hormonal methods of contraception or other
             forms of hormonal contraception that have comparable efficacy (failure rate <1%), for
             example hormone vaginal ring or transdermal hormone contraception Placement of an
             intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of
             contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with
             spermicidal foam/gel/film/cream/ vaginal suppository

         14. (Continued from Criteria 13) In case of use of oral contraception, women should have
             been stable on the same pill before taking study treatment. Note: Oral contraceptives
             are allowed but should be used in conjunction with a barrier method of contraception
             due to unknown effect of drug-drug interaction. Women are considered post-menopausal
             and not of child bearing potential if they have had 12 months of natural (spontaneous)
             amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of
             vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without
             hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy
             alone, only when the reproductive status of the woman has been confirmed by follow up
             hormone level assessment is she considered not of child bearing potential.

        Exclusion Criteria:

          1. Patients with known allergy or hypersensitivity to selinexor, sorafenib or any of its
             components.

          2. Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or
             psychiatric illness, which could place him/her at unacceptable risk.

          3. Patients who have had any major surgical procedure within 14 days of Day 1.

          4. Patients currently receiving any other standard or investigational therapy for the
             treatment of AML.

          5. Patients unwilling or unable to comply with the protocol.

          6. Patients receiving concomitant treatment with strong CYP3A4 inhibitors, unless such
             drugs are considered critical for the well being of the patient and not adequate
             alternatives are available. Strong CYP3A4 inhibitors include the following
             medications: itraconazole, ketoconazole, miconazole, voriconazole; amprenavir,
             atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir; ciprofloxacin,
             clarithromycin, diclofenac, doxycycline, enoxacin, isoniazid, ketamine, nefazodone,
             nicardipine, propofol, quinidine, telithromycin.

          7. Patients with any severe gastrointestinal or metabolic condition that could interfere
             with absorption of oral medications.

          8. Patients who are in blast transformation of chronic myeloid leukemia (CML). Prior MDS
             or CMML is acceptable.

          9. Patient has a concurrent active malignancy under treatment.

         10. Unstable cardiovascular function: • Symptomatic ischemia, or • Uncontrolled clinically
             significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic
             agents are excluded; 1st degree atrioventricular (AV) block or asymptomatic left
             anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded),
             or • Congestive heart failure (CHF) NYHA Class ≥ 3, or • Myocardial infarction (MI)
             within 3 months. • Left ventricular ejection fraction < 40 %. • Hypertension > 140 mm
             Hg systolic or > 90 mm Hg diastolic with or without antihypertensive therapy.

         11. Uncontrolled infection at the time of enrollment. Infections controlled on concurrent
             anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional
             guidelines is acceptable.

         12. Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be
             positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).

         13. Known human immunodeficiency virus (HIV) infection.

         14. Female subjects who are pregnant or breastfeeding.

         15. Acute promyelocytic leukemia.

         16. Any medical condition, which in the investigator's opinion, could compromise the
             patient's safety.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of Selinexor with Sorafenib
Time Frame:28 days
Safety Issue:
Description:MTD defined as the highest dose level with </= 1 out of 6 patients experience a dose limiting toxicity (DLT) during the first 28 days of treatment.

Secondary Outcome Measures

Measure:Composite CR (CRc) Rate defined as CR (complete remission) + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) within 3 months of treatment initiation
Time Frame:84 days, assessed following first three cycles of therapy of Selinexor with Sorafenib
Safety Issue:
Description:CRc Response criteria modified from International Working Group for AML. Responders obtain a Composite Complete Remission Rate (CRc) with or without cytogenetic response, hematologic improvements, and morphologic leukemia-free state. CRc rate is defined as the confirmed remission rate of all complete and incomplete CRs (i.e., CR+ CRp + CRi). CR: bone marrow regenerating normal hematopoietic cells & morphologic leukemia-free state, & ANC > 1×10^9/L, platelet count ≥100×10^9/L, & normal marrow differential with <5% blasts, & red blood cell (RBC) and platelet transfusion independent, no evidence of extramedullary leukemia. CRp: CR except for incomplete platelet recovery (<100×10^9/L). CRi: Same criteria for CR except incomplete hematological recovery with residual neutropenia (ANC ≤ 1 × 109/L) with or without thrombocytopenia (platelet count <100×109/L). No need to be RBC or platelet transfusion independent (modification to Cheson criteria).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Acute myeloid leukemia
  • AML
  • Relapsed/Refractory
  • FLT3-ITD mutation
  • FLT3-mutated high-risk myelodysplastic syndrome
  • MDS
  • Chronic Myelomonocytic Leukemia
  • CMML
  • Selinexor
  • KPT-330
  • Sorafenib
  • Nexavar
  • BAY 43-9006
  • FLT3-inhibitor therapy

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