Pilot Trial of Eltrombopag in Patients Undergoing Chemotherapy for Malignant Solid Tumors

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for study entry.

1. Persons aged ≥ 1 to ≤18 years of age.

2. Histologically confirmed solid tumors (including rhabdomyosarcoma, Ewings sarcoma,osteosarcoma, non- rhabdomyosarcoma soft tissue sarcoma, peripheral nerve sheathtumor, desmoplastic small round cell tumor, hepatoblastoma, hepatocellularcarcinoma, renal cell carcinoma, higher grade neuroblastoma, brain tumors (e.g.medulloblastoma), and other rare solid tumors.

3. Currently receiving cancer directed therapy for solid tumor or scheduled to startreceiving cancer directed therapy for solid tumor within 60 days.

4. Karnofsky Performance Status (KPS) performance status of 80% or greater.

5. Life expectancy ≥ 6 months.

6. Ability to swallow liquid solution/suspensions or tablets/capsules

7. Platelet count < 150,000µL

8. Blood chemistry levels defined by:

• Serum creatinine less than or equal to 2.5 × the upper limit of normal (ULN)range

• Total bilirubin level less than or equal to 1.5 × the upper limit of normal (ULN) range

• AST and ALT < 3 x upper limit of normal (ULN)

9. INR and aPTT less than or equal to 1.5 × ULN (for patients on anticoagulation theymust be receiving a stable dose for at least 1 week prior to first treatment)

10. Ability to understand and willingness to sign an informed consent form; orParent/Guardian with ability to understand and willingness to sign an informedconsent form.

11. Ability to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry.

1. Patients with known with hematologic malignancy diagnosis.

2. Contraindications to receiving chemotherapy.

3. Patients with history of thromboembolic disease or history of thrombophilic riskfactors.

4. History or current diagnosis of cardiac disease indicating significant risk ofsafety for patients participating in the study such as uncontrolled or significantcardiac disease, including any of the following:

• Recent myocardial infarction (within last 6 months),

• Uncontrolled congestive heart failure,

• Unstable angina (within last 6 months),

• Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustainedventricular tachycardia, and clinically significant second or third degree AVblock without a pacemaker.)

• Long QT syndrome, family history of idiopathic sudden death, congenital long QTsyndrome or additional risk factors for cardiac repolarization abnormality, asdetermined by the investigator.

5. Impaired cardiac function, defined as:

• Corrected QTc >450 msec using Fridericia correction (QTcF) on the screening ECG (using triplicate ECGs),

• Other clinically significant cardio-vascular disease (e.g., uncontrolledhypertension, history of labile hypertension),

• History of known structural abnormalities (e.g. cardiomyopathy).

6. Pregnant or lactating women.

7. Subjects with liver enzymes 5x upper limit of normal or liver cirrhosis (asdetermined by the investigator).

8. Patients with known history of HIV positivity.

9. Patient with known active or uncontrolled infections not responding to appropriatetherapy.

10. History of alcohol/drug abuse.

11. Concurrent participation in an investigational study within 30 days prior toenrollment or within 8 days (> than 5-half-lives)of the investigational product,whichever is longer. Note: parallel enrollment in a disease registry is permitted.

12. Known thrombophilic risk factors or history of thromboembolic disease. Exception:Subjects for whom the potential benefits of participating in the study outweigh thepotential risks of thromboembolic events, as determined by the investigator.

13. Known immediate or delayed hypersensitivity reaction to eltrombopag or itsexcipient.

14. Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using basic methods of contraception duringdosing of study treatment. Basic contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Male sterilization (at least 6 months prior to screening). The vasectomizedmale partner should be the sole partner for that subject.

• Barrier methods of contraception: Condom or Occlusive cap.

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception. In case of use of oral contraception women should have beenstable on the same pill for a minimum of 3 months before taking studytreatment.

15. Female subjects who are nursing or pregnant (positive serum or urine B-humanchorionic gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1.

16. Sexually active males unless they use a condom during intercourse while taking thedrug during treatment, and for 8 days (> 5 half-lives ) after stopping eltrombopagand for 5 half-lives after the last dose of chemotherapy treatment and should notfather a child in this period. A condom is required to be used also by vasectomizedmen as well as during intercourse with a male partner in order to prevent deliveryof the drug via semen.

17. Any condition that would prohibit the understanding or rendering of informedconsent.

18. Any condition that in the opinion of the investigator would interfere with thepatient's safety or compliance on trial.

19. Severe infection within 4 weeks prior to enrollment that in the opinion of theinvestigator would interfere with patient safety or compliance on trial.