Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma

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.

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.