Clinical Trials /

Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma

NCT03880123

Description:

The main purpose of this study is to establish a safe and tolerable dose combination (the "maximum tolerated dose") of selinexor and ixazomib when used together for the treatment of patients with certain types of advanced sarcoma. The study will enroll patients with advanced dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma and Ewing sarcoma. Future studies to further evaluate the safety and anti-cancer efficacy of this treatment for sarcoma will use the dose combination determined in this study.

Related Conditions:
  • Alveolar Soft Part Sarcoma
  • Dedifferentiated Liposarcoma
  • Ewing Sarcoma
  • Malignant Peripheral Nerve Sheath Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma
  • Official Title: A Phase I Study of the Selective Inhibitor of Nuclear Export (SINE) Selinexor in Combination With the Proteasome Inhibitor Ixazomib for the Treatment of Advanced Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: AAAS0199
  • NCT ID: NCT03880123

Conditions

  • Liposarcoma
  • Malignant Peripheral Nerve Sheath Tumors
  • Alveolar Soft Part Sarcoma
  • Ewing Sarcoma
  • Sarcoma

Interventions

DrugSynonymsArms
SelinexorKPT-330Selinexor/Ixazomib
IxazomibNinlaroSelinexor/Ixazomib

Purpose

The main purpose of this study is to establish a safe and tolerable dose combination (the "maximum tolerated dose") of selinexor and ixazomib when used together for the treatment of patients with certain types of advanced sarcoma. The study will enroll patients with advanced dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma and Ewing sarcoma. Future studies to further evaluate the safety and anti-cancer efficacy of this treatment for sarcoma will use the dose combination determined in this study.

Detailed Description

      Sarcoma is a rare form of cancer which originates from the soft tissues and bones of the
      body. There are more than 50 different types of sarcoma. The primary treatment approach for
      most types of advanced sarcoma involves chemotherapy, but newer treatment approaches are
      needed because chemotherapy is not curative, sometimes does not work well, and often has
      significant side effects.

      The purpose of this study is to evaluate a new treatment for certain types of sarcoma. The
      new treatment involves two oral targeted drugs used in combination: selinexor and ixazomib.
      Selinexor inhibits the transport of certain proteins between the nucleus and the cytoplasm of
      the cell. Ixazomib is part of a class of drugs called proteasome inhibitors. Currently,
      neither of these drugs is approved for the treatment of sarcoma. The researchers believe this
      combination treatment may work effectively for certain types of sarcoma based on encouraging
      laboratory research results. The types of sarcoma in which the treatment will be tested are:
      dedifferentiated liposarcoma, alveolar soft part sarcoma, malignant peripheral nerve sheath
      tumor, and Ewing sarcoma. The purpose of this study is to define doses of selinexor and
      ixazomib that are safe and tolerable for patients.
    

Trial Arms

NameTypeDescriptionInterventions
Selinexor/IxazomibExperimentalPatients will receive combination treatment with selinexor and ixazomib. The dose of ixazomib is fixed at 4 mg, whereas several different dose levels of selinexor may be evaluated. No patients will receive a placebo.
  • Selinexor
  • Ixazomib

Eligibility Criteria

        Inclusion Criteria:

          1. Signed written informed consent.

          2. Age ≥ 14 years

          3. Body surface area ≥ 1.2 m2

          4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

          5. Histologically confirmed de-differentiated liposarcoma, malignant peripheral nerve
             sheath tumor, alveolar soft part sarcoma or Ewing sarcoma. Liposarcomas with areas of
             well-differentiated disease are eligible if there is a biopsy-proven component of
             dedifferentiated liposarcoma. Pathology is reviewed at Columbia University Medical
             Center.

          6. Disease which is locally advanced and unresectable or metastatic. Disease which may be
             resected but with an associated level of morbidity deemed unacceptable by the treating
             clinician is considered eligible.

          7. Measurable disease as assessed by RECIST criteria version 1.1.

          8. Progression on, or intolerance to, at least one prior systemic regimen for sarcoma
             (including systemic treatment used in the adjuvant or neoadjuvant settings). For
             alveolar soft part sarcoma and dedifferentiated liposarcoma, there is no upper limit
             on the number of prior therapies that may have been received. For Ewing sarcoma and
             malignant peripheral nerve sheath tumor, patients may have received no more than 3
             prior lines of therapy (excluding systemic treatment used in the adjuvant or
             neoadjuvant settings).

          9. Acceptable organ and marrow function as defined below:

             Absolute neutrophil count (ANC) ≥ 1,500/mm3 Hemoglobin ≥ 8.5 g/dL Platelet count ≥
             100,000/mm3 Calculated creatinine clearance > 30 mL/min Total bilirubin ≤ 1.5 times
             upper limit of normal Aspartate Transaminase (AST) /Alanine Transaminase (ALT) ≤ 3.0
             times upper limit of normal

               -  Upper limit of normal is defined by the clinical laboratory performing the test.

               -  Creatinine clearance is obtained using the lean body mass formula (Modified
                  Cockcroft Gault)

               -  If transaminase elevation and/or bilirubin elevation is attributed to the
                  presence of liver metastases, a total bilirubin ≤ 2.5 times the upper limit of
                  normal and an Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 2.5
                  times the upper limit of normal are permissible. Patients with an elevated
                  bilirubin level that is attributed to an inherited disorder, such as Gilbert's
                  disease, may be enrolled at the discretion of the principal investigator.

               -  Patients may not receive platelet transfusions within 3 weeks of initiating
                  protocol therapy.

         10. Meet the following criteria regarding contraception:

        Female patients who:

          1. Are postmenopausal for at least 1 year before the screening visit, OR

          2. Are surgically sterile, OR

          3. If they are of childbearing potential, agree to practice 2 effective methods of
             contraception, at the same time, from the time of signing the informed consent form
             through 90 days after the last dose of study drug, OR

          4. Agree to practice true abstinence when this is in line with the preferred and usual
             lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
             symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
             contraception.)

        Male patients who: (must meet criteria even if surgically sterilized, i.e. after
        vasectomy):

          1. Agree to practice effective barrier contraception during the entire study treatment
             period and through 90 days after the last dose of study drug, OR

          2. Agree to practice true abstinence when this is in line with the preferred and usual
             lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation,
             symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
             contraception.)

        Exclusion Criteria:

          1. Received selinexor or another XPO1 inhibitor previously.

          2. Received ixazomib or another proteasome inhibitor previously.

          3. Currently pregnant or lactating.

          4. Prior malignancy that required treatment, or has shown evidence of recurrence (except
             for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during
             the 5 years prior to registration. Cancer treated with curative intent more than 5
             years previously and without evidence of recurrence is not an exclusion.

          5. Received any systemic anticancer therapy including investigational agents or radiation
             ≤3 weeks (or ≤5 half-lives of the drug, whichever is longer) prior to registration.
             Patients must have recovered to grade ≤ 1 or baseline from clinically significant
             adverse effects associated with prior anti-cancer therapies except for alopecia or
             controlled endocrinopathies.

          6. Major surgery within 2 weeks of first dose of study treatment.

          7. Any serious medical or psychiatric illness, medical condition or organ dysfunction
             which, in the investigator's opinion, could compromise patient safety or compliance
             with the protocol.

          8. Unstable cardiovascular function as defined by:

               1. Symptomatic ischemia, or

               2. Uncontrolled clinically significant conduction abnormalities (i.e., ventricular
                  tachycardia on anti-arrhythmia are excluded; 1st degree arterioventricular block
                  or asymptomatic left anterior fascicular block/right bundle branch block will not
                  be excluded), or

               3. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥3, or

               4. Myocardial infarction (MI) within 6 months

          9. Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before study enrollment. Prophylactic use of antibiotics and/or antivirals is
             acceptable.

         10. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus (HIV) positivity.

         11. History of clinically significant ocular disease manifest by visual defects or
             disturbances, including those caused by active glaucoma or cataracts, which have not
             been addressed by surgery or other corrective intervention. If necessary, an
             opthalmologic exam should be performed at screening.

         12. Inability to swallow tablets, clinically significant malabsorption syndrome, or any
             other GI disease or dysfunction that could interfere with absorption of study drugs.

         13. Presence of grade 3 peripheral neuropathy or grade 2 peripheral neuropathy with pain
             at any time during the screening period.

         14. Systemic treatment, within 14 days before initiation of study treatment, with strong
             CYP3A4 inducers (including, but not limited to rifampin, rifapentine, rifabutin,
             carbamazepine, phenytoin, phenobarbital) or use of St. John's wort.

         15. Unwillingness to comply with the study protocol and/or procedures.

         16. Central nervous system involvement.

         17. Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

         18. Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 30 days of the start of this trial and
             throughout the duration of this trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:14 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:Up to 2 years
Safety Issue:
Description:To establish the maximum tolerated dose combination for selinexor and ixazomib when used as a combination treatment for patients with dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma and Ewing sarcoma. The MTD is defined by the time to event continual reassessment method, a model-based dose finding study design.

Secondary Outcome Measures

Measure:Adverse Event (AE) Rate
Time Frame:Up to 2 years
Safety Issue:
Description:Adverse events will be collected from the day the patient receives the first dose of study treatment until 30 days after end-of-treatment. Adverse events will be reported by Common Terminology Criteria for Adverse Events (CTCAE criteria), stratified by grade.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Matthew Ingham

Trial Keywords

  • Liposarcoma
  • Malignant Peripheral Nerve Sheath Tumors
  • Alveolar Soft Part Sarcoma
  • Ewing Sarcoma
  • Selinexor
  • ixazomib
  • sarcoma
  • kpt-330

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