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

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 sheath tumor, desmoplastic small round cell tumor, hepatoblastoma, hepatocellular carcinoma, 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 start receiving 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 they must 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; or Parent/Guardian with ability to understand and willingness to sign an informed consent 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 risk factors.

4. History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac 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., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker.)
   • Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined 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., uncontrolled hypertension, 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 (as determined by the investigator).
8. Patients with known history of HIV positivity.
9. Patient with known active or uncontrolled infections not responding to appropriate therapy.
10. History of alcohol/drug abuse.
11. Concurrent participation in an investigational study within 30 days prior to enrollment 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 the potential risks of thromboembolic events, as determined by the investigator.
13. Known immediate or delayed hypersensitivity reaction to eltrombopag or its excipient.

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

    • Total 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
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total 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
    • Male sterilization (at least 6 months prior to screening). The vasectomized male 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 or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
15. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic 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 the drug during treatment, and for 8 days (> 5 half-lives ) after stopping eltrombopag and for 5 half-lives after the last dose of chemotherapy treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.
17. Any condition that would prohibit the understanding or rendering of informed consent.
18. Any condition that in the opinion of the investigator would interfere with the patient's safety or compliance on trial.
19. Severe infection within 4 weeks prior to enrollment that in the opinion of the investigator would interfere with patient safety or compliance on trial.