Metronomic Therapy for Pediatric Patients With Solid Tumors at High Risk of Recurrence

Most pediatric patients with solid tumors respond to initial high-dose, intensive therapy
and complete treatment in remission. High-risk patients however, frequently have recurrent
disease which is then treated with ad hoc regimens or early phase therapies with little
benefit to the patient. Metronomic therapy (MC), defined as lower dose continuous drug
exposure, has been successfully tested in pediatric leukemias with excellent results in
terms of improved outcome, toxicity profiles, and cost. MC has been applied to solid tumors
with little success, but has been implemented usually in the relapsed setting at a time of
high tumor burden and disease resistance. This protocol's overall objective is to improve on
historical outcome for high risk pediatric patients who are in remission by initiating MC
treatment after completion of front-line therapy.

This protocol 1) will treat patients when they have minimal disease burden, 2) will treat
patients with agents either not previously incorporated into front-line therapy or given in
a different manner and, 3) is designed to be given in the outpatient setting. The 4 agents
will take advantage of targeting frequently disrupted signaling pathways, epigenetic
abnormalities, and classical cell killing mechanisms. An analysis of cost will be undertaken
to help define part of the financial impact to families and on the health care system to
deliver this therapy. The hypothesis of this protocol is: Introduction of metronomic
treatment after completion of standard therapy for patients with high-risk, solid tumors in
remission will improve time to tumor progression compared with historical controls. The
primary and secondary goals (specific aims) of this protocol are: To determine the time to
tumor progression for patients at high-risk of relapse with solid tumors; To define and
describe the toxicity profile of the chemotherapy regimen; To determine the site(s) of
relapse for patients receiving treatment;To determine part of the cost of delivering
treatment; and finally to understand how this added therapy impacts quality of life.

Chemotherapy will be started within 6 weeks of completion of front-line treatment,
documentation of remission status and fulfillment of all eligibility criteria. Documentation
of remission will be by appropriate evaluations including history, physical examination,
laboratory testing and radiographic imaging and follow criteria for initial staging, when
appropriate.

There will be two study blocks. Each block will be of 21 days duration consisting of 14
treatment days followed by 7 rest days. The following block will start on day 22 of the
cycle. There will be 10 cycles of therapy (approximately 60 weeks) and each cycle is defined
by 42 days. Each block will be separated by a 1 week rest period (no chemotherapy) and
patients will be evaluated for disease status every two cycles of therapy. Therapy will
continue for 10 cycles or until patients relapse or are intolerant of therapy.

Block A consists of bevacizumab weekly X 2 weeks at 10 mg/kg, IV, on days 1 and 8, and oral
cyclophosphamide X 14 days at 25 mg/m2, on days 1-14. The maximum dose of cyclophosphamide
will be 50 mg. Block B will consist of temsirolimus weekly X 2 weeks, 25 mg/m2, IV, on days
22 and 29, and valproic acid, 5 mg/kg, by mouth, on days 22-35. Valproic acid trough levels
will be maintained at 75-100 ucg/mL by adjusting doses as appropriate. The rest periods are
on days 15-21 and 36-42.

Blocks of chemotherapy interrupted because of toxicity will not be repeated or time extended
to complete. The next block will be started when toxicity has improved to grade II or less
and if two blocks of treatment are interrupted for toxicity, dose reductions instituted as
defined in this protocol.

Additionally, subjects enrolled on MC and a control group will complete three quality of
life (PedsQL) instruments at three study time points: PedsQL Cancer Module, PedsQL Fatigue
Module, and the Present Functioning scale. These indicators will assess how added therapy
has impacted quality of life.

There are no investigational procedures, and no placebo involved in this protocol.

The potential benefits of this protocol are prolongation of remission status for the patient
with minimal toxicity, few anticipated hospitalizations and minimal additional cost of care.
Some patients may be cured as a result of this treatment. Should this study improve outcome
for this group of patients, the benefits to society would be great. Outcome for high risk
patients has stagnated for at least the last 10 years and additional high-dose chemotherapy
is unlikely to improve outcome because of poor tolerability (side effects). Studying some of
the cost associated with this treatment is important because of the lack of information on
out-patient care cost in general and to understand the economic impact on families and
society.

Inclusion Criteria:

1. The following solid tumors will be studied: rhabdomyosarcoma, osteosarcoma, Ewing
sarcoma, other soft tissue sarcomas

2. Other solid tumors fulfilling the remainder of eligibility criteria and available
historical data to determine time to tumor progression

3. Expected time to progression of < 2 years, based on historical data

4. All patients will have completed front-line therapy

5. All patients will be in remission from their primary diagnosis

6. All patients will start metronomic therapy within 6 weeks of completion of front-line
treatment

7. All patient will have recovered from previous toxicities

8. All patients or their parents/legal guardian will have signed an informed consent
document

9. All institutional eligibility criteria will be meet

10. Age: Patients must be ≥ 12 months and <31 years of age at the time of study entry

11. Patients must have had histologic verification of malignancy at original diagnosis

12. Patients must have a Lansky or Karnofsky performance status score of ≥ 50,
corresponding to ECOG categories 0, 1 or 2.

13. Adequate renal function defined as: Normal serum creatinine

14. Normal liver tests (ALT/AST/total bilirubin/triglycerides/cholesterol)

15. Recovered from all surgical procedures for at least 7 days (minor procedures) or 28
days (major procedures)

16. Adequate cardiac function defined as: Shortening fraction of ≥ 27% by echocardiogram,
or ejection fraction of ≥ 50% by radionuclide angiogram

17. Platelet count 100,000K/uL (transfusion independent), hemoglobin 8.0 g/dL

18. Adequate bone marrow function: Peripheral absolute neutrophil count (ANC) 1,000K/uL

19. Signed Informed Consent document and/or Assent document

Exclusion Criteria:

1. Female patients who are pregnant

2. Lactating females are not eligible unless they have agreed to discontinue
breastfeeding

3. Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained

4. Sexually active patients of reproductive potential are not eligible unless they have
agreed to use an effective contraceptive method for the duration of study
participation

5. Any primary central nervous system tumor

6. Any patient who has experienced relapsed or refractory disease or a second
malignancy.

7. Any patient not in remission