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

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by Jim Whitlock, The Hospital for Sick Children
Sponsor:
Collaborator:
C17 Council
Information provided by (Responsible Party):
Jim Whitlock, The Hospital for Sick Children
ClinicalTrials.gov Identifier:
NCT02303028
First received: November 25, 2014
Last updated: May 8, 2017
Last verified: May 2017
  Purpose
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 a fixed dose of pazopanib. The maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) will be evaluated for LDM topotecan in combination with pazopanib in children with recurrent or refractory solid tumours including CNS tumours. Pharmacokinetic and pharmacodynamic studies will be conducted to further define the exposure to and activity of LDM topotecan in combination with pazopanib.

Condition Intervention Phase
Solid Tumors Central Nervous System Tumors Drug: Topotecan and Pazopanib Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I and Enrichment Study of Low-dose Metronomic Topotecan and Pazopanib in Pediatric Patients With Recurrent or Refractory Solid Tumours Including CNS Tumours

Resource links provided by NLM:


Further study details as provided by Jim Whitlock, The Hospital for Sick Children:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of low dose metronomic (LDM)Topotecan [ Time Frame: Dose limiting toxicities (DLT) will be identified during the first cycle of therapy (28 days) ]
    MTD is dependent on the number of subjects who experience a DLT at a given dose level

  • Recommended phase 2 dose (RP2D) of LDM Topotecan [ Time Frame: Dose limiting toxicities (DLT) will be identified during the first cycle of therapy (28 days) ]
    The RP2D will be defined as the highest dose, at or below the MTD, at which the median number of cycles tolerated by subjects is ≥ 3.


Secondary Outcome Measures:
  • Anti-tumour activity of LDM Topotecan in combination with Pazopanib [ Time Frame: 24 months ]
    To preliminarily define the anti-tumour activity of LDM Topotecan in combination with pazopanib in pediatric solid tumours within the confines of a phase 1 study, and more specifically in cohorts of children with i) neuroblastoma and ii) rhabdomyosarcoma

  • Pharmacokinetics of LDM Topotecan and Pazopanib [ Time Frame: 24 months ]
    To characterize the pharmacokinetics of LDM Topotecan and Pazopanib, as well as any drug-drug interactions

  • Anti-angiogenic activity of LDM Topotecan and Pazopanib [ Time Frame: 24 months ]
    To assess the anti-angiogenic activity of this regimen by evaluating changes in plasma cytokines and angiogenic factors (CAF).


Estimated Enrollment: 42
Study Start Date: March 2015
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Topotecan and Pazopanib
Low dose Topotecan will be given metronomically at the dose level assigned at study entry, in combination with a fixed dose of Pazopanib
Drug: Topotecan and Pazopanib
Dose escalation of low-dose metronomic Topotecan with a fixed dose of Pazopanib
Other Names:
  • Hycamtin
  • Votrient

  Eligibility

Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION:

  1. Disease: Part 1-Relapsed or refractory solid tumours including CNS tumours; Part 2A-Neuroblastoma, Part 2B Rhabdomyosarcoma
  2. Measurable or evaluable disease
  3. No known curative therapy, or therapy proven to prolong survival with an acceptable QOL
  4. Organ Function Criteria

    • Peripheral ANC ≥ 1,500/μL; Plt ≥ 100,000/ and Hb ≥ 80 g/L (RBC transfusion permitted)
    • 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)
    • 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
    • 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 ≤ 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
    • Subjects with known history of seizures must have well-controlled seizures and not receiving enzyme-inducing anti-convulsants
    • INR ≤ 1.2 and PTT ≤ 1.2xULN
  5. 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.
  6. Ability to take liquid medication by mouth

EXCLUSION:

  1. Patients with DIPG, or known CNS metastases
  2. Pregnancy, breast feeding, or unwillingness to use effective contraception during the study
  3. 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.
  4. Subjects who have an uncontrolled infection or serious non-healing would, ulcer or bone fracture.
  5. Evidence of active bleeding, intratumoral haemorrhage, or bleeding diathesis, hemoptysis or any evidence of GI hemorrhage.
  6. 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.
  7. Previous, documented hypersensitivity reactions to topotecan or pazopanib
  8. History of abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days of study enrolment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02303028

Contacts
Contact: Rachel Polintan 416-813-7654 ext 228486 rachel.polintan@sickkids.ca
Contact: Gina J Lee 416-813-7654 ext 228486 ginaj.lee@sickkids.ca

Locations
Canada, Alberta
Alberta Children's Hospital Recruiting
Calgary, Alberta, Canada
Contact: Pina Giuliano         
Principal Investigator: Victor Lewis         
Canada, British Columbia
BC Children's Hospital Recruiting
Vancouver, British Columbia, Canada
Contact: Stephanie Badour         
Contact: Jessica Davis         
Principal Investigator: Rebecca Deyell         
Canada, Manitoba
CancerCare Manitoba Recruiting
Winnipeg, Manitoba, Canada
Contact: Rebekah Hiebert         
Contact: Kathy Hjalmarsson         
Principal Investigator: John Doyle         
Canada, Nova Scotia
IWK Health Centre Recruiting
Halifax, Nova Scotia, Canada
Contact: Lynn Russell         
Principal Investigator: Jason Berman         
Canada, Ontario
Children's Hospital of Eastern Ontario (CHEO) Recruiting
Ottawa, Ontario, Canada
Contact: Isabelle LaForest         
Principal Investigator: Donna Johnston         
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada
Contact: Gina Lee         
Principal Investigator: Daniel Morgenstern         
Canada, Quebec
CHU St. Justine Hopital Recruiting
Montreal, Quebec, Canada
Contact: Dominique Lafreniere         
Principal Investigator: Monia Marzouki         
Sponsors and Collaborators
The Hospital for Sick Children
C17 Council
Investigators
Study Chair: Jim Whitlock The Hospital for Sick Children
  More Information

Responsible Party: Jim Whitlock, Chief, Division of Haematology/Oncology, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT02303028     History of Changes
Other Study ID Numbers: 1000046233
IND.217 ( Other Identifier: NCIC CTG )
Study First Received: November 25, 2014
Last Updated: May 8, 2017

Keywords provided by Jim Whitlock, The Hospital for Sick Children:
Pediatric
CNS Tumor
Solid Tumour

Additional relevant MeSH terms:
Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Topotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 21, 2017