Phase I Dose Finding Study for Melatonin in Pediatric Oncology Patients With Relapsed Solid Tumors

• Melatonin (Drug), also known as SISU Melatonin

Primary outcomes

• Maximum tolerated daily dose of melatonin. [8 Weeks]

Secondary outcomes

• Number of dose limiting toxicities during 8 weeks of melatonin therapy. [8 Weeks]
• Peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of Melatonin. [8 Weeks]
• The quantity of cytokines will be measured during 8 weeks of melatonin therapy. [8 Weeks]
• Change from Baseline in weight after 8 weeks of therapy. [8 Weeks]

Sex: All, ages: 2 Years to 18 Years

Inclusion Criteria:

* Patients must be able to take medication by mouth either by swallowing, chewing or sublingual routes.
* Patients must have a documented life expectancy of ≥ 8 weeks.
* Patients must have histologic or radiographic evidence of a relapsed malignant solid tumor. Intrinsic brain stem tumors or optic pathway gliomas may be diagnosed by clinical and radiologic methods.
* Patient, parent, legal representative and/or guardian must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
* Minimum Weight Requirements: Dose level 1 - 22.2kg, Dose level 2 - 11.1kg, Dose level 3 - 5.6kg
* Patients must be taking a stable dose (with no additions, modifications or deletions) of chemotherapy started ≥ 14 days prior study enrollment.
* Prescribed Chemotherapy drug(s) must not be known to interact with melatonin
* Adequate Bone Marrow Function Defined as:

  1. Patients with solid tumors without bone marrow involvement:

     * Peripheral absolute neutrophil count (ANC) ≥ 1 x109/L
     * Platelet count ≥ 50 X 109/L (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
     * Hemoglobin ≥ 80 g/L (may receive RBC transfusions)
  2. Patients with known bone marrow metastatic disease are eligible for study but not evaluable for hematologic toxicity.

     * Must not be known to be refractory to red cell or platelet transfusions.
     * These patients do not need to meet the bone marrow function requirements, as hematological toxicity will not be measured due to metastatic disease.
* Adequate Liver Function Defined as:

  * Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) for age.
  * ALT ≤ 1.5 x ULN for age.

Exclusion Criteria:

* Chemotherapy: Melatonin inhibits the action of doxorubicin
* Growth factors that support white cell number administered ≤ 7 days prior to enrollment.
* Patients requiring corticosteroids who are not on a stable or decreasing dose of corticosteroid for ≥ 14 days.
* Patients prescribed immunosuppressant therapy that is not specifically utilized for chemotherapy purposes. Patient prescribed: Cyclosporine, Mycophenolate Mofetil HCL, Tacrolimus, Sirolimus and Azathioprine should be excluded
* Patients prescribed anti-coagulation therapy (Warfarin, Low Molecular Weight Heparin (LMWH), or System Heparin Therapy)
* Concomitant medications that are known CYP1A2 inhibitors interact with Melatonin.
* Patients prescribed megace, corticosteroids and periactin started ≤ 14 days prior to study enrollment.
* Patients taking the following medications: benzodiazepines, nifedipine, NSAID's, ASA and/or Beta Blockers
* Patients ≤ 7 days post-operative from any surgical procedure.
* Patients with any signs of active post-operative bleeding.
* Patients with an infection that is not responding to anti-microbial therapy.
* Any condition that would negatively impact effective gut absorption and/or swallowing of study medication.
* Patients in the opinion of the investigator may not be able to comply with study protocol requirements
* Patients already receiving melatonin are excluded from the study.
* Allergies to the medicinal and/or non-medicinal ingredients of melatonin which include: Melatonin, Calcium Salicate, Croscarmellose Sodium, IsoMalt, Magnesium Stearate, Microcrystalline Cellulose.
* As melatonin can cause fatigue, patients taking melatonin should refrain from driving or operating machinery within 5 hours of taking the melatonin.

• Donna Johnston, MD, Principal investigator, Children's Hospital of Eastern Ontario