Status:
COMPLETED
Phase I Dose Escalation Study of Topotecan and Pazopanib in Children With Recurrent/Refractory Solid Tumours
Lead Sponsor:
The Hospital for Sick Children
Collaborating Sponsors:
C17 Council
Conditions:
Solid Tumors
Eligibility:
All Genders
2-21 years
Phase:
PHASE1
PHASE2
Brief Summary
This is a phase I, dose escalation study where topotecan will be administered at lower doses given more frequently on a prolonged schedule (low dose metronomic; LDM), in combination with pazopanib adm...
Eligibility Criteria
Inclusion
- 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.
Exclusion
Key Trial Info
Start Date :
March 1 2015
Trial Type :
INTERVENTIONAL
Allocation :
ACTUAL
End Date :
June 17 2022
Estimated Enrollment :
30 Patients enrolled
Trial Details
Trial ID
NCT02303028
Start Date
March 1 2015
End Date
June 17 2022
Last Update
June 28 2022
Active Locations (10)
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1
Alberta Children's Hospital
Calgary, Alberta, Canada
2
BC Children's Hospital
Vancouver, British Columbia, Canada
3
CancerCare Manitoba
Winnipeg, Manitoba, Canada
4
Janeway Child Health Centre
St. John's, Newfoundland and Labrador, Canada