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Selinexor and Ixazomib for the Treatment of Locally Advanced Unresectable or Metastatic Sarcoma

Trial Status: Active

This phase I trial studies the side effects and best dose of selinexor when given together with ixazomib in treating patients with sarcoma that has spread from its original site of growth to nearby tissues or lymph nodes and is not amenable to surgical resection (locally advanced unresectable) or has spread to other places in the body (metastatic). Selinexor blocks the activity of a protein which transports certain molecules between different parts of a cell. Many cancers disrupt the normal location of proteins and other molecules to allow the cancer to keep growing. Ixazomib is proteasome inhibitor. Proteasomes are responsible for breaking down certain proteins within the cell. Ixazomib allows some proteins and molecules to remain active for a longer time. Selinexor may work better in treating sarcoma when combined with ixazomib.

Inclusion Criteria

  • Signed written informed consent
  • Body surface area >= 1.2 m^2 (as measured by Dubois or Mosteller)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • 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 (CUMC)
  • 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
  • Measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1
  • 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)
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Hemoglobin >= 8.5 g/dL
  • Platelet count >= 100,000/mm^3 * Patients may not receive platelet transfusions within 3 weeks of initiating protocol therapy
  • Calculated creatinine clearance > 30 mL/min * Creatinine clearance is obtained using the lean body mass formula (Modified Cockcroft Gault)
  • Total bilirubin =< 1.5 times upper limit of normal * Upper limit of normal is defined by the clinical laboratory performing the test * 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 aminotransferase (AST) and alanine aminotransferase (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
  • AST/ALT =< 3.0 times upper limit of normal * 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 AST and ALT =< 2.5 times the upper limit of normal are permissible
  • Meet the following criteria regarding contraception: * Female patients who: ** Are postmenopausal for at least 1 year before the screening visit, OR ** Are surgically sterile, OR ** 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 ** Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., 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): ** Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR ** Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)

Exclusion Criteria

  • Received selinexor or another XPO1 inhibitor previously
  • Received ixazomib or another proteasome inhibitor previously
  • Currently pregnant or lactating
  • 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
  • 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
  • Major surgery within 2 weeks of first dose of study treatment
  • 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
  • Unstable cardiovascular function as defined by: * Symptomatic ischemia, or * Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or * Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or * Myocardial infarction (MI) within 6 months
  • Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. Prophylactic use of antibiotics and/or antivirals is acceptable
  • Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positivity
  • 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 ophthalmologic exam should be performed at screening
  • Inability to swallow tablets, clinically significant malabsorption syndrome, or any other gastrointestinal (GI) disease or dysfunction that could interfere with absorption of study drugs
  • Presence of grade 3 peripheral neuropathy or grade 2 peripheral neuropathy with pain at any time during the screening period
  • 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
  • Unwillingness to comply with the study protocol and/or procedures
  • Central nervous system involvement
  • Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
  • 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

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Matthew Ingham
Phone: 212-305-5098

PRIMARY OBJECTIVE:

I. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) 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.

SECONDARY OBJECTIVE:

I. To further evaluate the safety and tolerability profile of the combination treatment.

EXPLORATORY OBJECTIVE:

I. To evaluate the preliminary efficacy of the combination treatment in patients with advanced dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma and Ewing sarcoma.

OUTLINE: This is a dose-escalation study of selinexor.

Patients receive selinexor orally (PO) on days 1, 8, 15, and 22 and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days and then every 3 months thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Matthew Ingham

  • Primary ID AAAS0199
  • Secondary IDs NCI-2019-05975
  • Clinicaltrials.gov ID NCT03880123