COZMOS:Phase I/Ib Trial of Combined 5'Azacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain/Solid Tumors

Prior treatment

• Patients may not be receiving any other investigational agents within 30 days prior to day 1 of protocol treatment
• Prior therapy with a DNA demethylase inhibitor
• Significant active cardiac disease within the previous 6 months including:
  • NYHA class 3 or 4 CHF
  • Unstable angina
  • Myocardial infarction
• Previous carboplatin exposure is not an exclusion criteria but previous allergic reaction to carboplatin will exclude enrolment.
• Patient must not require use of enzyme inducing anticonvulsants; patients who are receiving an enzyme inducing anticonvulsant must be able to switch to a non-enzyme inducing anticonvulsant such as Levetiracetam, Clobazam, Lacosamide, Valproate or Topiramate at least 2 weeks prior to study enrolment.

Other illness

• Evidence of cardiac toxicity (shortening fraction below 28%; shortening fraction measures and ratios the change in the diameter of the left ventricle between the contracted and relaxed states)
• Known or suspected hypersensitivity to azacitidine or mannitol carboplatin
• Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
• Active viral infection with HIV or hepatitis type B or C Patients with advanced malignant hepatic tumors
• Patients with advanced malignant hepatic tumors

Lab values

• Abnormal coagulation parameters (PT \>15 seconds, PTT\>40 seconds, and/or INR \>1.5)

Other

• Female patient who is pregnant or breast feeding (Lactating females must agree not to breast feed while taking azacitidine) or with childbearing potential and not willing to use a double method of contraception up to 3 months after the end of study treatment. Male patient who is not willing to use a barrier method of contraception up to 6 months after the end of study treatment.

• Greater than the age of 1 year and under age 18 at the time of study enrolment
• Recurrent or refractory brain or solid tumor, including recurrent or refractory ependymoma
• Tissue from diagnosis or resection prior to registration must be available (either flash frozen tissue or an FFPE block)
• Previous therapy with carboplatin will be permitted
• Failed first line treatment (surgery, radiation therapy or chemotherapy) and should not be eligible for treatment with curative potential.
• Be at least 4 weeks from the completion of myelosuppressive chemotherapy and/or biologic agents before starting day 1 of this study treatment
• Be at least 14 days from the completion of radiation therapy and MIBG before starting day 1 of this study treatment
• Be at least 3 months post hematopoetic stem cell rescue following myeloablative therapy before starting day 1 of this study treatment
• Must have visible disease on imaging. Resection of visible disease is permitted while on study after two cycles including achievement of a gross total resection. If a resection is performed while on study, fresh frozen tissue should be submitted for analysis.
• Concurrent medications will be limited to supportive medications/agents including but not limited to anti-emetics, steroids, analgesics and non-enzyme inducing anticonvulsants. Strong inducers of the P450 system will not be permitted. Other concurrent medications require approval of the study Sponsor.
• Ability of the parent and/or child to understand and the willingness to sign a written informed consent document
• Karnofsky ≥ 50 for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I for the Karnofsky-Lansky Scores). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Patients with posterior fossa syndrome/cerebellar mutism demonstrating clear improvement post-surgically can be enrolled based on physician discretion
• Adequate hepatic, renal, marrow and cardiac function as defined below within 28 days prior to cycle 1 day 1:
  • Serum creatinine within normal institutional limits or creatinine clearance greater than 60mL/min
  • Serum bilirubin \<1.5 times upper limit of institutional normal. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis
  • AST, ALT and Alkaline Phosphatase \<3 times upper limit of institutional normal. If liver metastases are present, then \<5 times upper limit of normal is permitted.
  • Normal QTc interval at screening ECG (baseline echocardiogram is not required)
  • Adequate marrow function defined below within 14 days prior to cycle 1 day 1:
  • Leukocytes greater than or equal to 1000 x106/L
  • Absolute neutrophil count greater than or equal to 0.75 x109/L
  • Platelets greater than or equal to 75 x109/L
  • Hemoglobin greater than or equal to 10g/dL (may be transfused).