Solid TumoursPhase 2NCT01956669
Pazopanib Paediatric Phase II Trial Children's Oncology Group (COG) in Solid Tumors
A Phase 2 study testing Pazopanib in people with Solid Tumours, run by Novartis Pharmaceuticals at 31 sites in 7 countries.
Trial summary
The study design was an open-label Phase II pediatric clinical study. The purpose of Study X2203 was to identify any efficacy signal in subjects with the disease subtypes under study, when treated with pazopanib monotherapy. Read more about this study
- Who is it for?
- Ages 1 year to 18 years
- Conditions the study is for
- Solid Tumours
- What is being tested?
- Pazopanib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 31 sitesin 7 countries
- Study dates
- 8 Oct 2014to 5 Nov 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Subjects must be at least 1 and less than or equal to 18 years of age at the time of study entry.
- Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse - a) Rhabdomyosarcoma, b) Non-rhabdomyosarcomatous Soft Tissue Sarcoma (including desmoplastic small round cell tumor), c) Ewing Sarcoma / Peripheral Primitive Neuroectodermal Tumor (PNET), d) Osteosarcoma, e) Neuroblastoma (Measurable), f) Neuroblastoma (Evaluable), g) Hepatoblastoma.
- Patient must have disease that has either relapsed or is refractory to prior therap
- Patients who will be receiving the tablet formulation must have a body surface area (BSA) >= 0.84 m^2 (square meter) at baseline.
- Patients must have radiographically measurable disease (with the exception of neuroblastoma), Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm).
- Patients with neuroblastoma who do not have measurable disease but have iodine-131 - meta-iodobenzylguanidine positive (MIBG+) evaluable disease are eligible.
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- Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use Karnofsky for subjects >= 16 years of age and Lansky for subjects <= 16 years of age.
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
- Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
- At least 7 days must have elapsed since the 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 peg-filgrastim.
- At least 7 days must have elapsed since the completion of therapy with a biologic agent. For biologic agents that have known adverse events occurring beyond 7 days after administration, the period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
- Subjects may have received bevacizumab, VEGF-Trap, or other VEGF blocking tyrosine kinase inhibitors, provided that they did not progress while receiving one of these agents. Subjects may not have previously received pazopanib.
- At least 21 days must have elapsed since the completion of the last dose of VEGF-Trap, and at least 7 days since a VEGF blocking tyrosine kinase inhibitor. Subjects must have recovered from any VEGF blocking drug-related toxicity (e.g., proteinuria).
- > = 21 days must have elapsed from infusion of last dose of antibody and toxicity related to prior antibody therapy must have recovered to Grade <= 1.
- Radiotherapy: >=2 weeks must have elapsed since local palliative radiotherapy (XRT) (small port); >=3 months must have elapsed if prior Traumatic Brain Injury (TBI), craniospinal XRT or if >=50% radiation of pelvis; >=6 weeks must have elapsed if other substantial bone marrow irradiation was given.
- No evidence of active graft versus host disease and >=2 months must have elapsed since transplant or rescue
- Adequate Bone Marrow Function defined as peripheral absolute neutrophil count (ANC) >=1000/ microlitre (µL), platelet count >= 75,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment); and hemoglobin >= 8.0 grams (g)/decilitre (dL), may receive red blood cell (RBC) transfusions. Subjects with bone marrow involvement will be eligible for study (provided they meet the criteria) but will not be evaluable for hematologic toxicity.
- Adequate Renal and Metabolic Function defined as creatinine clearance or radioisotope Glomerular filtration rate (GFR) >= 70 millilitre (mL)/ (min)/1.73 meter (m)^2 or A serum creatinine based on age/gender as follows, age 1 to < 2 years (male-0.6 milligrams (mg)/dL, female-0.6 mg/dL), age 2 to < 6 years (male-0.8 mg/dL, female-0.8 mg/dL), age 6 to < 10 years (male-1 mg/dL, female-1 mg/dL), age 10 to < 13 years (male-1.2 mg/dL, female-1.2 mg/dL), age 13 to < 16 years (male-1.5 mg/dL, female-1.4 mg/dL), age >= 16 years (male-1.7 mg/dL, female-1.4 mg/dL), urine creatinine ratio of <1 or a urinalysis that is negative for protein; or, 24-hour urine protein level < 1000 mg/dL, adequate thyroid function ,no more than Grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium and phosphorous.
- Adequate Liver Function defined as total bilirubin <=1.5 x upper limit of normal (ULN) for age, serum glutamic-pyruvic transaminase (SGPT) Alanine transaminase (ALT) <=2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L), Serum albumin >=2 g/dL. Must not have active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment). NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. No known positivity of hepatitis B surface antigen (HBsAg), or of positive hepatitis C antibody.
- Adequate Cardiac Function defined as shortening fraction of >=27% by echocardiogram (while not receiving medications for cardiac function), or ejection fraction of >= 50% by gated radionuclide study (while not receiving medications for cardiac function), the corrected QTc interval by Bazett's formula (QTcB) <450 milliseconds (msec), and must not have a history of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation.
- Adequate Blood Pressure Control defined as a blood pressure (BP) <= the 95th percentile for age, height, and gender measured, subjects on stable doses of no more than one anti-hypertensive medication, with a baseline BP <= 95th percentile for age, height and gender, will be eligible.
- Central Nervous System (CNS) Function defined as subjects with a known history of seizures must have well-controlled seizures and may not be receiving enzyme-inducing anti-convulsants, CNS toxicity <= Grade 2.
- Adequate Coagulation defined as prothrombin time (PT) and partial thromboplastin time (PTT) <= 1.2 x upper limit of normal and an international normalized ratio (INR) <= 1.2.
Who cannot join
- Pregnant or breast-feeding women are not eligible for this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method beginning at the signing of the informed consent until at least 2 weeks after the last dose of the study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate. Study drug may also potentially be secreted in milk and therefore breastfeeding women are excluded.
- Males (including those who have had vasectomies) with partners who can become pregnant will need to use birth control while on this study, as will their partner. Men are advised to use condoms during sexual intercourse while on study drug and continue to use adequate contraception for at least 2 weeks after the last dose of protocol therapy.
- Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible.
- Patients who are currently receiving another investigational drug are not eligible.
- Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
- Patients who are currently receiving more than one anti-hypertensive medication (Grade 3) or whose blood pressure is not well controlled are not eligible for study enrollment.
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- Patients must not be on therapeutic anticoagulation (Warfarin [coumadin] and/or low molecular weight heparin are prohibited). Prophylactic anticoagulation (i.e. intraluminal heparin) of venous or arterial access devices is allowed.
- Patients receiving drugs with a known risk of torsades de pointes are not eligible.
- Patients 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 enrollment.
- Patients who are unable to swallow tablets or liquid are not eligible.
- Patients who have an uncontrolled infection are not eligible.
- Patients will be excluded if any of the following are present, evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis; History (within 6 months prior to study enrollment) of arterial thromboembolic events, including transient ischemic attack (TIA) or cerebrovascular accident (CVA); history (within 6 months prior to study enrollment) of pulmonary embolism, deep venous thrombosis (DVT), or other venous thromboembolic event; history of clinically significant bleeding within 6 weeks prior to study enrollment.
- Patients with known involvement of the CNS by malignancy will be excluded.
- Patients who have had or are planning to have the following invasive procedures will be excluded- Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy (Subcutaneous port placement or central line placement is not considered major surgery but must be placed greater than 48 hours from planned Day 1 of therapy); Core biopsy within 7 days prior to Day 1 therapy; Fine needle aspirate or central line placement within 48 hours prior to Day 1therapy.
- Patients with serious or non-healing wound, ulcer, or bone fracture.
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study enrollment.
- Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
Trial locations and contacts
31 sites in 7 countries.
31 sites in 7 countries
United States24 sites
Novartis Investigative Site
Chapel Hill, North Carolina, 27599
Novartis Investigative Site
Charlotte, North Carolina, 28203
Novartis Investigative Site
Chicago, Illinois, 60611
Novartis Investigative Site
Cincinnati, Ohio, 45229
Novartis Investigative Site
Dallas, Texas, 75235
Novartis Investigative Site
Fort Worth, Texas, 76104
Novartis Investigative Site
Hackensack, New Jersey, 07601
Novartis Investigative Site
Hartford, Connecticut, 06106
Novartis Investigative Site
Houston, Texas, 77030
Novartis Investigative Site
Indianapolis, Indiana, 46202
Novartis Investigative Site
Kansas City, Missouri, 64108
Novartis Investigative Site
Long Beach, California, 90801
Novartis Investigative Site
Madera, California, 93638-8762
Novartis Investigative Site
Minneapolis, Minnesota, 55404
Novartis Investigative Site
Nashville, Tennessee, 37212
Novartis Investigative Site
New York, New York, 10032
Novartis Investigative Site
Norfolk, Virginia, 23507
Novartis Investigative Site
Orange, California, 92868
Novartis Investigative Site
Orlando, Florida, 32806
Novartis Investigative Site
Palo Alto, California, 94304
Novartis Investigative Site
San Francisco, California
Novartis Investigative Site
Seattle, Washington, 98105
Novartis Investigative Site
St Louis, Missouri, 63110
Novartis Investigative Site
St. Petersburg, Florida, 33701
Canada2 sites
Novartis Investigative Site
Montreal, Quebec, H3T 1C5
Novartis Investigative Site
Toronto, Ontario, M5G 1X8
About this study
Official title: A Phase II Study of Pazopanib GW786034, NSC# 737754 in Children, Adolescents and Young Adults With Refractory Solid Tumors
The study design was an open-label Phase II pediatric clinical study. The purpose of Study X2203 was to identify any efficacy signal in subjects with the disease subtypes under study, when treated with pazopanib monotherapy. Furthermore, it was to define the toxicities of pazopanib in children, as well as examine biological markers, e.g. cytokines and angiogenic factors, that could help further characterize any response of pazopanib in children. Pazopanib was administered as monotherapy in tablet and powder suspension formulations at daily doses of 450 mg/m2/dose or 225 mg/m2/dose, respectively. The first 6 enrolled subjects receiving oral suspension formulation were assessed for tolerability and extended PK sampling; and, only if pazopanib was tolerated, subsequent subjects were enrolled at the same starting dose with the suspension. Dose escalation was not permitted. For the tablet, a dosing nomogram was used based on the subject's BSA. Dose reduction was dependent upon the toxicity of pazopanib and disease status of the infants, toddlers, children, adolescents, and young adults. Subjects could be as young as 1 year-old infants to screen for enrollment. Subjects were assessed for initial response after 8 weeks of treatment prior to Cycle 3. A cycle was defined as 28 days of pazopanib treatment with no rest period between cycles. Treatment was administered continuously once daily. Treatment was to be discontinued if there was evidence of disease progression, unacceptable treatment-related toxicity, pregnancy. Histological classification was an important diagnostic inclusion in these subjects with a wide variety of refractory solid tumors, i.e. 7 different tumor types and each being a cohort.
Read the detailed description
The study design included a hierarchical 2-stage tumor response assessment with each cohort independent from one other. First, an initial 10 subjects were enrolled into each cohort. In the event of ≥ 1 response in any of these initial subjects, an additional 10 subjects may be enrolled in that cohort to proceed. In the event of ≥ 3 responses, the agent was considered effective. However after end of-stage 1, study enrollment stopped due to insufficient antitumor activity. Subjects who discontinued study treatment were followed for survival status. The study was to continue accruing data and thus, remained open for approximately 1 year from Last Subject Last Visit (LSLV).
- Conditions
- Solid Tumours
- Being tested
- Pazopanib
- Keywords
- VEGF, Pazopanib, Sarcoma, GW786034, Refractory Solid Tumors
- Medical subject headings
- Sarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PazopanibDrug
Also called GW786034
Pazopanib was supplied as a series of aqueous film-coated tablets containing 200 mg (oval-shaped, white, packaged in bottles containing 34 tablets each), and 400 mg (oval-shaped, white, packaged in bottles containing 68 tablets each). Pazopanib Powder for Oral Suspension was a white to slightly colour powder supplied to the clinical sites in amber glass (United State Pharmacopeia (USP) Type III) bottles with child-resistant closures. Each bottle contains 5 g of pazopanib.
| Study group | Role | What they receive |
|---|---|---|
| Pazopanib | Experimental | All subjects were treated with pazopanib GW786034 tablets at a dose of 450 mg/m^2/dose or as a powder in suspension at a dose of 225 mg/m^2/dose. The maximum daily dose administered was to be 800 mg for the tablet and 400 mg for suspension. If 225 mg/m^2/dose was not tolerated (>=2 DLTs in 6 evaluable subjects), the dose for subjects who required suspension was reduced to 160 mg/m^2/dose. A cycle was defined as 28 days with no rest periods between cycles. Receives: Drug: Pazopanib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants Achieving Objective Response Rate (ORR) in Subjects' With Tumors of Primary Interest (RMS, NRSTS or Ewing Sarcoma/pPNET)
ORR was defined as the percentage of participants achieving either a Complete Response (CR) or partial Response (PR) based on the Investigator review. The responses were assessed by CT or MRI based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST1.1). CR, disappearance of all target and non-target lesions; PR, at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study enrollment, also no new lesion or progression of any non-target measurable lesion. Confirmation was based on the disease assessment at 1 cycle or at the next scheduled visit after the initial response. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 55 months
Secondary outcomes (13)
Percentage of Participants Achieving Objective Response Rate (ORR) in Subjects' With Tumors of Secondary Interest (Osteosarcoma, mNeuroblastoma, eNeuroblastoma or Hepatoblastoma)
ORR was defined as the percentage of participants achieving either a Complete Response (CR) or partial Response (PR) based on the Investigator review. For solid tumors with measurable diseases, such as osteosarcoma, the responses was based on RECIST1.1. CR, disappearance of all target and non target lesions; PR, at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study enrollment, also no new lesion or progression of any non-target measurable lesion. For neuroblastoma with bone marrow response, morphology was determined by hematoxylin and eosin staining of the marrow and aspirates. For neuroblastoma MIBG+ only, the responses was assessed using Curie scale for lesion scoring; For hepatoblastoma, assessment may have included the serum AFP response, in addition to the RECIST1.1 methodology. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 55 months
Progression Free Survival (PFS) as Assessed by the Investigator by Cohort
PFS was defined as the interval between the date of first dose of study medication and the earliest date of disease progression or death due to any cause. Disease progression was based on radiographic evidence, and assessments made by the investigator. According to RECIST1.1, disease progression was defined as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions. For participants who did not progress or die, PFS was censored at the date of last adequate assessment or date of last adequate assessment prior to initiation of new anti-cancer therapy. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 59 months
Time to Progression (TTP) by Cohort
The TTP was defined as the interval between the date of first dose of protocol therapy and the earliest date of disease progression or death due to disease under study. Subjects were considered to have progressive disease if they had documented progression based on radiologic assessment as determined by investigator review. According to RECIST1.1, disease progression was defined as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 59 months
Percentage of Participants Achieving Clinical Benefit Rate (CBR) by Cohort
CBR was defined as the percentage of participants achieving either a confirmed complete response (CR) or confirmed partial response (PR) or Stable Disease (SD) for at least two protocol scheduled disease assessments based on RECIST1.1. CR, disappearance of all target and non-target lesions; PR, at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study enrollment, also no new lesion or progression of any non-target measurable lesion; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 55 months
Duration of Response (DOR) by Cohort
DoR was defined as the time from initial response to the first documented disease progression or death due to any cause, and was determined only for those participants from the mITT population with a confirmed response (CR or PR). Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 59 months
Overall Survival (OS) by Cohort
OS was defined as the time from the first dose of the study medication until death due to any cause. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 61 months
Area Under the Plasma Concentration-time Curve Calculated From Time 0 to 8 h Postdose (AUC0-8h) and Calculated to the Last Quantifiable Concentration Point (AUClast) of Pazopanib by Cohort
AUC0-8h and AUClast were calculated using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) and the LLOQ was 0.100 µg/mL. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
Measured: Day 1 of Cycle 1 (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose); Cycle 1 Day 15 ± 1 day (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose)
Observed Maximum Plasma Concentration (Cmax) of Pazopanib by Cohort
Cmax was calculated using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) and the LLOQ was 0.100 µg/mL. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
Measured: Day 1 of Cycle 1 (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose); Cycle 1 Day 15 ± 1 day (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose)
Time to Reach Peak or Maximum Concentration (Tmax) of Pazopanib by Cohort
Tmax was calculated using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) and the LLOQ was 0.100 µg/mL. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.
Measured: Day 1 of Cycle 1 (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose); Cycle 1 Day 15 ± 1 day (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose)
Pazopanib Steady-state Trough (Ctrough) Levels for Participants With Drug-related Grade 2 and Above Hypertension
The relationship between toxicity (including hypertension) and pharmacokinetic parameters (pazopanib trough concentration) was analyzed. Only descriptive analysis performed.
Measured: From date of first dose of study treatment up to 61 months
Number of Participants With Genetic Alterations by Low and High Values of VEGFA and VEGFR1
The frequency of genetic alterations observed in participants was presented by high and low baseline plasma levels for Vascular endothelial growth factor A (VEGF-A) and Vascular endothelial growth factor receptor 1 (VEGFR-1) biomarkers. The VEGFA and VEGFR1 levels above the median were classified as high and participants with median levels or below were classified as low. Only descriptive analysis performed for participants presenting with a genetic alteration.
Measured: predose Cycle 1 Day 1, Cycle 2 Day 1
Summary for Plasma Biomarkers Levels on Cycle 1 Day 1 and Cycle 2 Day 1 by Cohort
The following biomarker parameters were analyzed: proto-oncogene c-KIT (c-KIT), Fibroblast growth factor (FGF), Placental growth factor PGF), Angiopoietin-1 receptor (TIE2), Vascular endothelial growth factor A (VEGF-A), Vascular endothelial growth factor C (VEGF-C), Vascular endothelial growth factor D (VEGF-D), Vascular endothelial growth factor receptor 1 (VEGFR-1) and Vascular endothelial growth factor receptor 2 (VEGFR-2)). Only descriptive analysis performed.
Measured: predose Cycle 1 Day 1, Cycle 2 Day 1
Summary for Change From Baseline Levels of Plasma Biomarkers by High and Low Pazopanib Steady State Trough Concentration and Cohort
Participants with steady state trough concentration median levels for the following biomarker parameters (proto-oncogene c-KIT (c-KIT), Fibroblast growth factor (FGF), Placental growth factor PGF), Angiopoietin-1 receptor (TIE2), Vascular endothelial growth factor A (VEGF-A), Vascular endothelial growth factor C (VEGF-C), Vascular endothelial growth factor D (VEGF-D), Vascular endothelial growth factor receptor 1 (VEGFR-1) and Vascular endothelial growth factor receptor 2 (VEGFR-2)) above the median levels were classified as high or below median levels were classified as low. Only descriptive analysis performed.
Measured: predose Cycle 1 Day 1, Cycle 2 Day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2013 (estimated)
- Study start8 Oct 2014
- Primary completion5 Nov 2019
- Study completion5 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Solid TumoursStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The study design included a hierarchical 2-stage tumor response assessment with each cohort independent from one other. * Cohort 1: rhabdomyosarcoma (RMS) * Cohort 2: non-rhabdomyosarcomatous soft tissue sarcoma (NRSTS) * Cohort 3: Ewing sarcoma/pPNET * Cohort 4: osteosarcoma * Cohort 5: measurable neuroblastoma (mNeuroblastoma) * Cohort 6: evaluable neuroblastoma (eNeuroblastma) * Cohort 7: hepatoblastoma
- Masking
- None (open label)
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Children's Oncology Group
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01956669
- Sponsor's protocol ID
- 116731
- Other IDs
- 2013-003595-12, CPZP034X2203
- Status last verified
- Jul 2020
- First submitted
- 1 Aug 2013
- Last updated
- 12 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Pazopanib GW786034, NSC# 737754 in Children, Adolescents and Young Adults With Refractory Solid Tumors
- ClinicalTrials.gov ID
- NCT01956669
- Acronym / sponsor ID
- 116731
- Conditions
- Solid Tumours
- Keywords
- VEGF, Pazopanib, Sarcoma, GW786034, Refractory Solid Tumors
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 57 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Collaborators
- Children's Oncology Group
- Study start
- 8 Oct 2014 (actual)
- Primary completion
- 5 Nov 2019 (actual)
- Study completion
- 5 Nov 2019 (actual)
- First posted
- 8 Oct 2013 (estimated)
- Results
- Posted 12 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study design was an open-label Phase II pediatric clinical study. The purpose of Study X2203 was to identify any efficacy signal in subjects with the disease subtypes under study, when treated with pazopanib monotherapy. Furthermore, it was to define the toxicities of pazopanib in children, as well as examine biological markers, e.g. cytokines and angiogenic factors, that could help further characterize any response of pazopanib in children. Pazopanib was administered as monotherapy in tablet and powder suspension formulations at daily doses of 450 mg/m2/dose or 225 mg/m2/dose, respectively. The first 6 enrolled subjects receiving oral suspension formulation were assessed for tolerability and extended PK sampling; and, only if pazopanib was tolerated, subsequent subjects were enrolled at the same starting dose with the suspension. Dose escalation was not permitted. For the tablet, a dosing nomogram was used based on the subject's BSA. Dose reduction was dependent upon the toxicity of pazopanib and disease status of the infants, toddlers, children, adolescents, and young adults. Subjects could be as young as 1 year-old infants to screen for enrollment. Subjects were assessed for initial response after 8 weeks of treatment prior to Cycle 3. A cycle was defined as 28 days of pazopanib treatment with no rest period between cycles. Treatment was administered continuously once daily. Treatment was to be discontinued if there was evidence of disease progression, unacceptable treatment-related toxicity, pregnancy. Histological classification was an important diagnostic inclusion in these subjects with a wide variety of refractory solid tumors, i.e. 7 different tumor types and each being a cohort.
Detailed description
The study design included a hierarchical 2-stage tumor response assessment with each cohort independent from one other. First, an initial 10 subjects were enrolled into each cohort. In the event of ≥ 1 response in any of these initial subjects, an additional 10 subjects may be enrolled in that cohort to proceed. In the event of ≥ 3 responses, the agent was considered effective. However after end of-stage 1, study enrollment stopped due to insufficient antitumor activity. Subjects who discontinued study treatment were followed for survival status. The study was to continue accruing data and thus, remained open for approximately 1 year from Last Subject Last Visit (LSLV).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The study design included a hierarchical 2-stage tumor response assessment with each cohort independent from one other. * Cohort 1: rhabdomyosarcoma (RMS) * Cohort 2: non-rhabdomyosarcomatous soft tissue sarcoma (NRSTS) * Cohort 3: Ewing sarcoma/pPNET * Cohort 4: osteosarcoma * Cohort 5: measurable neuroblastoma (mNeuroblastoma) * Cohort 6: evaluable neuroblastoma (eNeuroblastma) * Cohort 7: hepatoblastoma
| Arm | Type | Receives |
|---|---|---|
| Pazopanib | Experimental | Drug: PazopanibAll subjects were treated with pazopanib GW786034 tablets at a dose of 450 mg/m^2/dose or as a powder in suspension at a dose of 225 mg/m^2/dose. The maximum daily dose administered was to be 800 mg for the tablet and 400 mg for suspension. If 225 mg/m^2/dose was not tolerated (>=2 DLTs in 6 evaluable subjects), the dose for subjects who required suspension was reduced to 160 mg/m^2/dose. A cycle was defined as 28 days with no rest periods between cycles. |
Who may qualify
- Ages
- 1 year to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (23 listed)
- Subjects must be at least 1 and less than or equal to 18 years of age at the time of study entry.
- Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse - a) Rhabdomyosarcoma, b) Non-rhabdomyosarcomatous Soft Tissue Sarcoma (including desmoplastic small round cell tumor), c) Ewing Sarcoma / Peripheral Primitive Neuroectodermal Tumor (PNET), d) Osteosarcoma, e) Neuroblastoma (Measurable), f) Neuroblastoma (Evaluable), g) Hepatoblastoma.
- Patient must have disease that has either relapsed or is refractory to prior therap
- Patients who will be receiving the tablet formulation must have a body surface area (BSA) >= 0.84 m^2 (square meter) at baseline.
- Patients must have radiographically measurable disease (with the exception of neuroblastoma), Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm).
Key exclusion criteria (17 listed)
- Pregnant or breast-feeding women are not eligible for this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method beginning at the signing of the informed consent until at least 2 weeks after the last dose of the study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate. Study drug may also potentially be secreted in milk and therefore breastfeeding women are excluded.
- Males (including those who have had vasectomies) with partners who can become pregnant will need to use birth control while on this study, as will their partner. Men are advised to use condoms during sexual intercourse while on study drug and continue to use adequate contraception for at least 2 weeks after the last dose of protocol therapy.
- Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible.
- Patients who are currently receiving another investigational drug are not eligible.
- Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PazopanibAlso: GW786034Pazopanib was supplied as a series of aqueous film-coated tablets containing 200 mg (oval-shaped, white, packaged in bottles containing 34 tablets each), and 400 mg (oval-shaped, white, packaged in bottles containing 68 tablets each). Pazopanib Powder for Oral Suspension was a white to slightly colour powder supplied to the clinical sites in amber glass (United State Pharmacopeia (USP) Type III) bottles with child-resistant closures. Each bottle contains 5 g of pazopanib. | Drug | Pazopanib |
Primary outcome
Percentage of Participants Achieving Objective Response Rate (ORR) in Subjects' With Tumors of Primary Interest (RMS, NRSTS or Ewing Sarcoma/pPNET)
Time frame: From date of first dose of study treatment up to 55 months
ORR was defined as the percentage of participants achieving either a Complete Response (CR) or partial Response (PR) based on the Investigator review. The responses were assessed by CT or MRI based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST1.1). CR, disappearance of all target and non-target lesions; PR, at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study enrollment, also no new lesion or progression of any non-target measurable lesion. Confirmation was based on the disease assessment at 1 cycle or at the next scheduled visit after the initial response. Only descriptive analysis performed.
13 secondary outcomes
Percentage of Participants Achieving Objective Response Rate (ORR) in Subjects' With Tumors of Secondary Interest (Osteosarcoma, mNeuroblastoma, eNeuroblastoma or Hepatoblastoma)
Time frame: From date of first dose of study treatment up to 55 months
Progression Free Survival (PFS) as Assessed by the Investigator by Cohort
Time frame: From date of first dose of study treatment up to 59 months
Time to Progression (TTP) by Cohort
Time frame: From date of first dose of study treatment up to 59 months
Percentage of Participants Achieving Clinical Benefit Rate (CBR) by Cohort
Time frame: From date of first dose of study treatment up to 55 months
Duration of Response (DOR) by Cohort
Time frame: From date of first dose of study treatment up to 59 months
Overall Survival (OS) by Cohort
Time frame: From date of first dose of study treatment up to 61 months
Area Under the Plasma Concentration-time Curve Calculated From Time 0 to 8 h Postdose (AUC0-8h) and Calculated to the Last Quantifiable Concentration Point (AUClast) of Pazopanib by Cohort
Time frame: Day 1 of Cycle 1 (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose); Cycle 1 Day 15 ± 1 day (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose)
Observed Maximum Plasma Concentration (Cmax) of Pazopanib by Cohort
Time frame: Day 1 of Cycle 1 (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose); Cycle 1 Day 15 ± 1 day (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose)
Time to Reach Peak or Maximum Concentration (Tmax) of Pazopanib by Cohort
Time frame: Day 1 of Cycle 1 (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose); Cycle 1 Day 15 ± 1 day (0, 0.5, 1, 2, 4, 6 and 8 hours post-dose)
Pazopanib Steady-state Trough (Ctrough) Levels for Participants With Drug-related Grade 2 and Above Hypertension
Time frame: From date of first dose of study treatment up to 61 months
Number of Participants With Genetic Alterations by Low and High Values of VEGFA and VEGFR1
Time frame: predose Cycle 1 Day 1, Cycle 2 Day 1
Summary for Plasma Biomarkers Levels on Cycle 1 Day 1 and Cycle 2 Day 1 by Cohort
Time frame: predose Cycle 1 Day 1, Cycle 2 Day 1
Summary for Change From Baseline Levels of Plasma Biomarkers by High and Low Pazopanib Steady State Trough Concentration and Cohort
Time frame: predose Cycle 1 Day 1, Cycle 2 Day 1
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
31 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pazopanib in people with Solid Tumours, run by Novartis Pharmaceuticals at 31 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 31 sites in United States, Canada, Czechia, France, Hungary and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants Achieving Objective Response Rate (ORR) in Subjects' With Tumors of Primary Interest (RMS, NRSTS or Ewing Sarcoma/pPNET) (time frame: From date of first dose of study treatment up to 55 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Aug 2020.