Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)

A Randomized, Placebo-Controlled Pilot Study of Genistein Supplementation in Pediatric Cancer Patients Receiving Myelosuppressive Chemotherapy

Toxicities related to pediatric cancer treatment can lead to significant illness, organ damage, treatment delays, increased health care cost, and decrease in quality of life. Such toxicities are largely due to tissue damage sustained by chemotherapy, and strategies designed to limit such cellular damage to normal tissues may reduce therapy-related morbidity and mortality. In addition to their in vitro and in vivo anti-cancer effects, naturally occurring soy isoflavones have anti-inflammatory and anti-oxidant properties, and have been shown to reduce side effects of therapy in adult oncology clinical trials. This study will examine the effect of genistein, the major isoflavone component in soybeans and the most extensively studied of the soy isoflavones, on short-term side effects of myelosuppressive chemotherapy in pediatric cancer patients. Subjects will be randomized to receive either: a) 30 mg genistein daily throughout chemotherapy Cycles 1 and 2 and placebo during chemotherapy Cycles 3 and 4; or b) placebo daily during chemotherapy Cycles 1 and 2 and 30 mg genistein daily during chemotherapy Cycles 3 and 4. Investigators hypothesize that subjects will have fewer short-term therapy-related side effects during cycles of chemotherapy given in conjunction with genistein supplementation than cycles given with placebo.

This is a multi-center, randomized, double blind, placebo-controlled crossover study to evaluate the effect of soy isoflavones on the short term untoward effects of myelosuppressive chemotherapy used to treat pediatric cancers. Newly diagnosed cancer patients aged 1-21 years will be registered to the study and informed consent will be obtained prior to any study-related procedures. Stratification will be based on length of chemotherapy cycles, between 14 day and 21 day cycles. Within strata registered subjects will be randomized 1:1 to one of two schedules:

Arm A: Subjects will receive genistein daily throughout chemotherapy cycles 1 and 2, and placebo during chemotherapy cycles 3 and 4

Arm B: Subjects will receive placebo daily throughout chemotherapy cycles 1 and 2, and genistein during chemotherapy cycles 3 and 4

Subjects will be assessed for safety and efficacy during each cycle with clinical labs, cytokine panels, and physical exams. Drug compliance will be monitored by use of a patient diary as well as monitoring of serum genistein levels. Adverse events will be monitored starting on Cycle 1 Day 1 through 30 days following the last day of protocol therapy (genistein/placebo).

Inclusion Criteria

1. Newly diagnosed solid tumor or lymphoma with histological verification

2. Age 1 - 21 years at time of diagnosis

3. Karnofsky/Lanksy performance score of ≥ 50

4. Able to tolerate enteral medication administration

5. Planned chemotherapeutic regimen for a patient must meet all of the following criteria:

   • A known myelosuppressive regimen which includes at least two of the following agents: actinomycin, carboplatin, cisplatin, cyclophosphamide, daunorubicin, doxorubicin, etoposide, ifosfamide, topotecan
   • At least four consecutive cycles
   • Cycle length is either 14 or 21 days
   • Regimen must either alternate myelosuppressive chemotherapeutic agents in an X-Y-X-Y format, such that the same chemotherapy is given every other cycle (e.g. vincristine/doxorubicin/cyclophosphamide │ ifosfamide/etoposide), or repeat the same chemotherapeutic agents each cycle in an X-X-X-X format (e.g. repeated cycles of cisplatin/etoposide/bleomycin). Courses eligible for this trial may occur at any time during treatment provided that they are consecutive and follow the one of the described patterns. Non-myelosuppressive anti-neoplastic treatments will not be considered for the purposes of determining eligibility. Questions regarding whether or not a patient's chemotherapy plan meets inclusion criteria will be decided by the Study Chair.

6. Informed consent or parental permission and assent obtained prior to trial-related activities

7. Able and willing to comply with all study related procedures

8. Women of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Exclusion Criteria

1. Known allergy to soy or any soy-based food or supplement
2. Unable or unwilling to discontinue consuming prohibited soy-based food or supplements while participating in this study
3. Pre-existing neutropenia or neutrophil qualitative or quantitative disorder
4. Pre-existing cytopenia or bone marrow failure syndrome
5. History of gastric or duodenal ulcers or hyperacidity syndromes
6. History of Human Immunodeficiency Virus (HIV)
7. Has an active infection requiring systemic therapy
8. Planned treatment does not include myelosuppressive chemotherapy
9. Enrolled on a therapeutic or supportive care clinical trial within the last 30 days
10. Current acute or chronic leukemia diagnosis
11. Requires medication dosing via an enteral feeding tube that terminates in the duodenum or jejunum. (Enteral feeding tubes that terminate in the stomach are acceptable for study medication delivery.)
12. Pregnant or breastfeeding woman
13. Incarceration
14. Secondary malignancy, i.e. the cancer for which the patient is presently or will be receiving treatment may not be a malignancy related to prior cancer therapy
15. Any condition which might be worsened by estrogen, such as breast cancer, uterine cancer, ovarian cancer, endometriosis or uterine fibroids
16. Any condition, in the investigator's opinion, that would compromise patient safety or study outcomes
17. Anyone who, in the investigator's discretion, would be unwilling or unable to comply with study procedures