Phase I Dose Escalation Study of Topotecan and Pazopanib in Children With Recurrent/Refractory Solid Tumours

INCLUSION:

• Disease: Part 1-Relapsed or refractory solid tumours with histological verification of malignancy. Patients with CNS tumours are not eligible. Parts 2A and 2B - histological verification of one of the following solid tumours: Neuroblastoma or Rhabdomyosarcoma
• Measurable or evaluable disease
• No known curative therapy, or therapy proven to prolong survival with an acceptable QOL
• Performance status: Lansky or Karnofsky ≥ 50%
• ORGAN FUNCTION CRITERIA Bone Marrow Function

• Peripheral ANC ≥ 1.5x109/L; Plt ≥ 100x109/L and Hgb ≥ 80 g/L (RBC transfusion permitted) Renal Function
• Measured creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2, OR a serum creatinine based on age/gender that meets the criteria outlined in the protocol
• Urinalysis negative for protein, urine protein:creatinine ratio of ≤ 1, OR a 24-hour urine protein < 1000 mg/dL
• <Gr.1 abnormalities of K, Ca (confirmed by ionized Ca),Mg or Ph (supplementation allowed) Liver Function
• Total serum bilirubin ≤ 1.5xULN for age
• SGPT (ALT) ≤ 2.5 x ULN and SGOT (AST) ≤ 2.5 x ULN
• Serum albumin ≥ 20 g/L Cardiac Function
• Adequate systolic ventricular function (LVSF≥ 27% or LVEF ≥ 50%)
• QTc measured by ECG must be < 450 msec.
• No history of MI, severe or unstable angina, peripheral vascular disease, or familial QTc prolongation Blood Pressure
• Blood pressure ≤ 95th percentile for age, height, gender AND one of:
• No current anti-hypertensive therapy, OR on stable doses of no more than one anti-hypertensive medication CNS Function
• Subjects with known history of seizures must have well-controlled seizures and not receiving enzyme-inducing anti-convulsants Coagulation Function
• INR ≤ 1.2 and PTT ≤ 1.2xULN
• Prior Therapy

• Myelosuppressive chemo must not have been given within 3 weeks of study enrolment (6 weeks if nitrosourea)
• At least 7 days must have elapsed since completion of therapy with a growth factor that supports platelet or white cell number or function. At least 14 days must have elapsed after receiving pegfilgrastim.
• Biologic anti-neoplastic agent (including VEGF-blocking TKI) must not have been administered within 7 days of study enrolment
• At least 3 half lives of the monoclonal antibody must have elapsed since the last dose administered
• ≥ 2 weeks must have elapsed since local palliative XRT (small port); > 13 weeks since prior total body irradiation (TBI), craniospinal XRT or > 50% radiation of pelvis; or > 6 weeks if other substantial bone marrow irradiation
• ≥ 8 weeks must have elapsed since MIBG therapy for neuroblastoma
• At least 60 days must have elapsed from autologous or allogeneic stem cell transplant with no signs of GVHD.
• At least 28 days from major surgery and wounds must be healed. At least 7 days from open and/or core biopsy.
• Ability to take liquid medication by mouth

EXCLUSION:

• Patients with CNS tumours or known CNS metastases
• Pregnancy, breast feeding, or unwillingness to use effective contraception during the study
• Subjects currently receiving:

• Corticosteroids who haven't been on a stable or decreasing dose of corticosteroid for 7 days prior
• Another investigational drug; other anti-cancer agents or radiation therapy
• More than one medication for blood pressure control
• Therapeutic anticoagulation, including systemic use of warfarin, heparin, or low molecular weight heparin at any dose
• Aspirin, and/or ibuprofen, or other NSAIDs
• Drugs metabolized through several of the specific P450 cytochrome isoforms and those receiving drugs with a known risk of torsades de pointes
• Subjects who require thyroid replacement therapy are not eligible if they have not been receiving a stable replacement dose for at least 4 weeks prior to study enrolment.
• Subjects who have an uncontrolled infection or serious non-healing would, ulcer or bone fracture.
• Evidence of active bleeding, intratumoral haemorrhage, or bleeding diathesis, hemoptysis or any evidence of GI hemorrhage.
• History (within 26 weeks prior to study enrolment) of arterial thromboembolic events (including TIA, CVA, or MI), pulmonary embolism, DVT or other venous thromboembolic event.
• Evidence of tumour-related or other thrombus at time of enrolment
• Major surgical procedure, laparoscopic procedure or significant traumatic injury within 28 days prior to Day 1 therapy. Open or core biopsy within 7 days prior to Day 1 of therapy. Fine needle aspirate within 48 hours prior to Day 1 therapy.
• Previous, documented hypersensitivity reactions to topotecan or pazopanib
• History of abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days of study enrolment.
• QTc > 450msec on baseline ECG or history of familial prolonged QTc syndrome
• History of inflammatory lung disease secondary to exposure to mTOR or tyrosine kinase inhibitors.