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

NCT02303028 | Completed Phase 1 DMC

• 2 other identifiers: 1000046233IND.217
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 10

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 administered in a specific dose range. 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. Pharmacokinetic and pharmacodynamic studies will be conducted to further define the exposure to and activity of LDM topotecan in combination with pazopanib.

Conditions

Solid Tumors

Keywords

Pediatric; Solid Tumour

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) of low dose metronomic (LDM)Topotecan

  MTD is dependent on the number of subjects who experience a DLT at a given dose level

  Dose limiting toxicities (DLT) will be identified during the first cycle of therapy (28 days)

• Recommended phase 2 dose (RP2D) of LDM Topotecan

  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.

  Dose limiting toxicities (DLT) will be identified during the first cycle of therapy (28 days)

Secondary Outcomes (3)

• Anti-tumour activity of LDM Topotecan in combination with Pazopanib

  24 months

• Pharmacokinetics of LDM Topotecan and Pazopanib

  24 months

• Anti-angiogenic activity of LDM Topotecan and Pazopanib

  24 months

Study Arms (1)

Topotecan and Pazopanib

EXPERIMENTAL

Low dose Topotecan will be given metronomically in combination with Pazopanib at the dose level assigned at study entry

Drug: Topotecan and Pazopanib

Interventions

Topotecan and Pazopanib DRUG

Low-dose metronomic Topotecan and Pazopanib will be escalated as per the dose escalation schema.

Also known as: Hycamtin, Votrient

Topotecan and Pazopanib

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• C17 Council: collaborator

Study Sites (10)

Alberta Children's Hospital

Calgary, Alberta, Canada

Location

BC Children's Hospital

Vancouver, British Columbia, Canada

Location

CancerCare Manitoba

Winnipeg, Manitoba, Canada

Location

Janeway Child Health Centre

St. John's, Newfoundland and Labrador, Canada

Location

IWK Health Centre

Halifax, Nova Scotia, Canada

Location

McMaster Children's Hospital

Hamilton, Ontario, Canada

Location

Children's Hospital, London Health Sciences Centre

London, Ontario, Canada

Location

Children's Hospital of Eastern Ontario (CHEO)

Ottawa, Ontario, Canada

Location

Hospital for Sick Children

Toronto, Ontario, Canada

Location

CHU St. Justine Hopital

Montreal, Quebec, Canada

Location

MeSH Terms

Interventions

Topotecan; pazopanib

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Study Officials

• Jim Whitlock

  The Hospital for Sick Children

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Division of Haematology/Oncology

Study Record Dates

• First Submitted: November 25, 2014
• First Posted: November 27, 2014
• Study Start: March 1, 2015
• Primary Completion: June 17, 2022
• Study Completion: June 17, 2022
• Last Updated: June 28, 2022

Record last verified: 2022-06

Locations

CA (10)