Melatonin Supplementation for Cancer-related Fatigue in Patients Receiving Radiotherapy

This is a double-blind, placebo-controlled trial wherein subjects with breast cancer will be randomized to receive either 20 mg oral melatonin or placebo the night before their first radiotherapy (RT), nightly throughout their RT, and for an additional 2 weeks following the completion of their RT. After informed consent is obtained from eligible subjects, they will then be electronically randomized on a 1:1 ratio to melatonin treatment or placebo. The subjects will be stratified according to treatment duration (less than 3 weeks; equal to or greater than 3 weeks) and prior chemotherapy.

Subjects will be randomized to receive either melatonin or placebo. Subjects will receive 20-mg oral melatonin or placebo the night before their first RT treatment, each night throughout the course of RT treatment, and for 2 weeks following the completion of RT. Patients with localized breast cancer will receive standard-of-care RT as determined by the treating physician. The RT regimens include: (1) 1 week of accelerated (APBI); (2) 3-4 weeks of an accelerated hypofractionation RT schedule; and (3) 6-8 weeks of a standard RT schedule. No additional concomitant medication or supportive care guidelines are required for this study. Subjects will receive daily melatonin or placebo beginning the night before their course of RT and for an additional 2-week period that extends beyond the conclusion of their RT. Subjects will be given a Study Diary to record their use of study medication. Patients will be followed for 60 days after removal from the study treatment or until death, whichever occurs first. Patients removed from the study treatment for unacceptable adverse events (AEs) will be followed until resolution or stabilization of the adverse event.

Eligibility Criteria:
Inclusion Criteria

1. Ambulatory outpatients with breast (including ductal carcinoma in situ \[DCIS\]) cancer.
2. Patients to be treated with RT for curative intent.
3. Women ≥18 years of age.
4. Eastern Cooperative Oncology Group (ECOG) performance status \<3 (Appendix 4).
5. Hemoglobin ≥ 9 g/dL
6. Either post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control during study treatment and for 3 months afterwards.
7. Subjects who are currently taking melatonin must discontinue melatonin for 5 days before enrolling in the study.
8. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

1. Fatigue brought on by conditions other than cancer such as (the indicated tests are required only if that mechanism of fatigue is suspected):

   * uncontrolled hypothyroidism (TSH \>10 IU)
   * hypercalcemia (calcium \>11 mg/dL) Calcium (Ca) = Serum Calcium (SerumCa) + 0.8 \* (NormalAlbumin - PatientAlbumin)
   * decompensated congestive heart failure
   * chronic obstructive pulmonary disease requiring oxygen replacement
2. Patients with a creatinine clearance \<30 mL/min
3. Aspartate aminotransferase (AST) \> 3X upper limit of normal (ULN)
4. Alanine aminotransferase (ALT) \> 3X ULN
5. Bilirubin \> 1X ULN
6. Use of systemic steroids, or other pharmacological agents such as methylphenidate for cancer-related fatigue
7. Current use of American ginseng, remelteon, or warfarin.
8. Depression ≥ grade 2 (CTCAE v4.0)