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

Open Label Single Arm Prospective Pilot Trial of Eltrombopag in Patients 1 Year to 18 Years of Age Undergoing Intensive Chemotherapy for Malignant Solid Tumors (CCPO011)

Primary Objective: To assess safety of eltrombopag in pediatric patients undergoing intensive chemotherapy for malignant solid tumors.

Secondary Objectives: To assess the efficacy of eltrombopag in increasing platelet count up to 2 weeks after completion of chemotherapy in pediatric patients undergoing intensive chemotherapy for malignant solid tumors.

Hypothesis: The hypothesis is that eltrombopag an oral thrombopoietin receptor agonist will increase the platelet count safely and efficaciously in children having chemotherapy induced thrombocytopenia while on therapy for solid tumors.

Eltrombopag is an orally administered, small molecule thrombopoietin receptor (TPO-R) agonist that stimulates platelet production by a mechanism similar, but not identical to endogenous TPO. Eltrombopag interacts with the transmembrane domain of the TPO-R (also known as C-MPL) leading to increased platelet production (Erickson-Miller, 2010; Sun et al, 2012).

Eltrombopag is indicated for the treatment of thrombocytopenia in adult and pediatric patients one year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag has also been approved for the treatment of thrombocytopenia in adult patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy and for the treatment of cytopenias in adult patients with severe aplastic anemia (SAA) who have had insufficient responses to immunosuppressive therapy.

This is an open label, single center pilot trial of eltrombopag in pediatric patients receiving cancer directed therapy for solid tumors. The purpose of this study is to explore the platelet supportive care effects and safety of eltrombopag in pediatric patients (ages one to 18 years of age) undergoing intensive chemotherapy for malignant solid tumors. The primary endpoint will be to determine the safety of eltrombopag in pediatric patients undergoing intensive chemotherapy for malignant solid tumors using CTCAE v5.0 criteria. The secondary endpoint will be to determine the efficacy of eltrombopag in pediatric patients undergoing intensive chemotherapy for malignant solid tumors. These objectives will be assessed by evaluating drug-related toxicities, the platelet response in patients and the proportion of subjects receiving eltrombopag who are platelet transfusion-free during the time period of chemotherapy.

The study will enroll 10 subjects with histologically confirmed solid tumors, including but not limited to rhabdomyosarcoma, Ewing 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, medulloblastoma, or other rare malignant solid tumors.

The cancer directed therapy will be part of standard treatment for each patient and will consist of two to four cycles of chemotherapy (or as many as clinically indicated per physician discretion) to reduce tumor burden, followed by surgery in the majority of cases, and/or radiation in a minority of cases, or both in rare cases at various times in the course of treatment. After recovery from the surgery and/or radiation, chemotherapy and eltrombopag will be resumed until completion. Each cycle of chemotherapy will be approximately two to four weeks (14 to 28 days) in length with chemotherapy administered for one to five days per cycle. The duration of chemotherapy varies by regimen and underlying malignancy.

Patients will initiate eltrombopag on the first day following the completion of chemotherapy for each cycle (e.g., chemo is administered on Days 1-5, eltrombopag to start on Day 6). Eltrombopag will be administered daily and the dose will be age dependent (see Table 5). Children less than 6 years of age will receive a starting dose of 25 mg by mouth once daily, taken on empty stomach one hour before or two hours after a meal. For children greater than or equal to 6 years of age, the starting dose will be 75 mg by mouth once daily. Doses shall be reduced in patients of Asian ancestry (e.g., Japanese, Chinese, Taiwanese, or Korean): for those patients greater than or equal to 6 years of age, the starting dose will be 50 mg by mouth once daily and for those patients less than 6 years old, the starting dose will be 12.5 mg by mouth once daily. Eltrombopag will be continued until the platelets are at least 100,000/µL after the nadir.

Subjects will be recruited from the UC Davis Comprehensive Cancer Center or when they are admitted to UC Davis Children's Hospital.

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 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.