PAZOFOS: Phase Ib and Phase II Trial of Pazopanib +/- Fosbretabulin in Advanced Recurrent Ovarian Cancer (PAZOFOS)
The first part of this study is to find the recommended dosages of a combination of two drugs: pazopanib and fosbretabulin, which will be given to female patients with relapsed ovarian cancer.
The second part of the study involves comparing the recommended dose of pazopanib and fosbretabulin in combination against pazopanib alone in female patients with relapsed ovarian cancer to determine whether the combination is more beneficial that pazopanib on it's own.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase Ib and Randomised Phase II Trial of Pazopanib With or Without Fosbretabulin in Advanced Recurrent Ovarian Cancer|
- Phase Ib: Dose Limiting Toxicities of Dose of Pazopanib and Fosbretabulin [ Time Frame: 4 weeks after starting treatment (1 cycle) ] [ Designated as safety issue: Yes ]To determine the dose of Pazopanib and Fosbretabulin in combination by recording Dose Limiting Toxicities (DLTs) at each cohort level as categorised by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Assessment of toxicity will take place over the 4-week period that constitutes one cycle
- Phase II: Progressive disease [ Time Frame: Progressive disease (average of 4 months from start of treatment) measured by RECIST ] [ Designated as safety issue: No ]
To determine whether fosbretabulin and pazopanib in combination improves progression free survival compared to pazopanib alone measured by RECIST
Computed Tomography (CT) scans are taken every 8 weeks for the first 6 cycles and evaluated by the Response Evaluation Criteria In Solid Tumours (RECIST) criteria.
After 6 cycles of fosbretabulin and pazopanib patients will receive pazopanib alone and CT scans will be undertaken every 3 months (12 weeks).
- Phase I: Biomarker changes on a cohort-by cohort basis [ Time Frame: Samples taken within the 4 weeks prior to the first dose of drug and during first cycle (weeks 2 and 3) and then at progressive disease (average of 4 months from start of treatment) ] [ Designated as safety issue: No ]Circulating markers of angiogenesis: VEGFA (Vascular Endothelial Growth Factor), VEGFR2, Ang1 (Angiopoietin), Ang2 and Tie (Tyrosine kinase with immunoglobulin-like and EGF-like domains) 2 will be measured from samples taken pre-treatment and during cycle 1 of treatment
- Phase Ib and Phase II: Safety and Toxicity profile of Pazopanib and Fosbretabulin in combination [ Time Frame: Adverse Events recorded within the 4 weeks prior to the first dose of drug is administered and during the first 3 weeks of a 4 week cycle of treatment for 6 cycles, then every month until progressive disease (average of 4 months from start of treatment) ] [ Designated as safety issue: Yes ]
The Phase Ib component is estimated to last approximately 9 months with the total duration of the trial expected to last 45 months. All adverse events will be recorded and categorised by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
Patients will receive up to six cycles of fosbretabulin and pazopanib after which treatment will be continued with pazopanib alone until progressive disease. It is estimated each patient will be on the trial for approximately 4 months.
- Phase II: Biomarker signature for Progression Free Survival [ Time Frame: Samples taken within the 4 weeks prior to first dose of drug ] [ Designated as safety issue: No ]
To investigate whether the pre-treatment biomarker signature can predict which patients have a response and a longer progression free survival
Circulating markers of angiogenesis: VEGFA, VEGFR2, Ang1, Ang2 and Tie 2 will be measured by ELISA and compared to progression free survival data
- Phase II: Response rates by RECIST and GCIG CA-125 criteria [ Time Frame: Progressive disease (average of 4 months from start of treatment) measured by RECIST and CA125 biomarkers ] [ Designated as safety issue: No ]
The response rate in the pazopanib and combination arms according to RECIST and Gynaecologic Cancer Intergroup (GCIG) Cancer Antigen 125 (CA-125) criteria
CT scans every every 8 weeks for the first 6 cycles then every 3 months until progressive disease (average of 4 months from start of treatment). CA125 taken twice per cycle for first 6 and then every month until progressive disease
- Phase II: Biomarker response in combination arm [ Time Frame: Samples taken within the 4 weeks prior to the first dose of drug, Cycle 1 (weeks 2 and 3) and at progression (average of 4 months from start of treatment) ] [ Designated as safety issue: No ]
To investigate whether biomarkers can demonstrate additivity of the combination in comparison with single agent pazopanib
Circulating markers of angiogenesis: VEGFA, VEGFR2, Ang1, Ang2 and Tie 2 will be measured from samples taken pre-treatment and during cycle 1 of treatment and at progression.
Circulating endothelial progenitor cells (CEPCs) from these samples will be counted.
|Study Start Date:||September 2014|
|Estimated Study Completion Date:||June 2018|
|Estimated Primary Completion Date:||June 2018 (Final data collection date for primary outcome measure)|
Experimental: Phase Ib/ II: Fosbretabulin & Pazopanib
Fosbretabulin and Pazopanib in combination. The phase II dose of both drugs will be determined by the Phase Ib component which is a dose finding exercise.
Fosbreatabulin dose will be in the range of 45mg/m2- 60 mg/m2 delivered by infusion every week for 3 weeks of a 4 week cycle for a maximum of 6 cycles.
Pazopanib will be either 600 mg or 800mg taken orally each day of 28 day cycle until disease progression
Tyrosine Kinase Inhibitor
Other Names:Drug: Fosbretabulin
Vascular Disrupting Agent
Other Name: Fosbretabulin tromethamine
Active Comparator: Phase II: Pazopanib
Pazopanib 800mg taken orally each day of 28 day cycle until disease progression
Tyrosine Kinase Inhibitor
Ovarian cancer is the fourth biggest contributor to female cancer mortality, accounting for 4% of all malignancies diagnosed in women. In the United Kingdom (UK), there are seven thousand new cases of ovarian cancer annually and four thousand two hundred deaths from the disease. The standard treatment approach currently consists of surgical debulking and chemotherapy, usually based around a combination of carboplatin and paclitaxel. Most ovarian cancers are initially chemo-responsive however the majority of patients whose disease initially responds subsequently develop recurrent disease.
Once patients recur, treatment options become less numerous and less effective. Progression free survival rates for platinum-sensitive disease are only about 13 months and the outlook for patients with platinum-resistant disease is much worse.
This study is exploring a new combination of drugs fosbretabulin, a vascular disrupting agent and pazopanib, a tyrosine kinase inhibitor. There is scientific rational for combining these two types of drugs as they should be able to work in combination through contrasting mechanisms of action.
The first part of the study is a dose finding exercise with cohorts of patients being given drugs with in combination until the recommended dose of both drugs is found. Patients in each cohort will be monitored closely for safety and drug toxicity.
The second part of the study has a randomised component where patients will receive the combination of drugs or pazopanib alone with the aim to determine whether there is an advantage in progression free survival for patients that receive pazopanib and fosbretabulin. This will be monitored by RECIST.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02055690
|Contact: Heather Driscoll||+44 (0) 161 918 7414||Heather.Driscoll@christie.nhs.uk|
|The Royal Marsden NHS Foundation Trust||Recruiting|
|London, United Kingdom, SM2 5PT|
|Principal Investigator: Susana Banerjee|
|The Christie NHS Foundation Trust||Recruiting|
|Manchester, United Kingdom, M20 4BX|
|Principal Investigator: Andrew Clamp|
|Mount Vernon Cancer Centre (East and North Herts NHS Trust)||Recruiting|
|Middlesex, United Kingdom, HA6 2RN|
|Principal Investigator: Gordon Rustin|
|Study Chair:||Gordon Jayson||The Christie National Health Service (NHS) Foundation Trust|
|Study Chair:||Gordon Rustin||East and North Herts NHS Trust|