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Ovarian NeoplasmsPhase 1/2PAZOFOSNCT02055690

PAZOFOS: Phase Ib and Phase II Trial of Pazopanib +/- Fosbretabulin in Advanced Recurrent Ovarian Cancer

A Phase 1/2 study testing Pazopanib and Fosbretabulin in people with Ovarian Neoplasms and Neoplasms, Ovarian, run by The Christie NHS Foundation Trust at 10 sites in United Kingdom.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Pazopanib and Fosbretabulin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
21 participants
Where
10 sitesUnited Kingdom
Study dates
Sep 2014to 24 Nov 2017
Phase
Phase 1/2
Are there results?
None posted in the registry

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 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Advanced, progressive, recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma, which has recurred following at least one platinum-containing regimen.
  • Progressive disease according to RECIST 1.1 or GCIG criteria within 3-12 months of completing platinum containing therapy, although this need not be the immediately preceding regimen.
  • World Health Organisation (WHO) performance status of 0 or 1 (Appendix 1).
  • Measurable disease (RECIST 1.1 (Appendix 2) or Progressive Disease (PD) according to CA125 GCIG criteria with non-measurable disease on CT scan.
  • Life expectancy of at least 12 weeks.
  • Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient receives the first dose of Investigational Medicinal Product (IMP):
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  • Haemoglobin (Hb) ≥ 90 g/L
  • Absolute neutrophil count ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Serum potassium within normal range
  • Bilirubin ≤ 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 2.5 x ULN unless raised due to hepatic metastatic disease in which case up to 5 x ULN is permissible
  • Either: Calculated creatinine clearance ≥ 40 mL/min (uncorrected value) Or: Isotope clearance measurement ≥ 40 mL/min (corrected)
  • Activated partial thromboplastin time (aPTT) ≤ 1.2 x ULN
  • Prothrombin Time (PT) or International normalised ratio (INR) ≤ 1.3 x ULN
  • Urine protein dipstick of less than or equal to 2+, or if 2+ or greater the patient must have a 24 hour urinary protein value of less than 2 g.
  • Clinically euthyroid.
  • Aged 18 years or over at the time of consent.
  • Written (signed and dated) informed consent and capable of co-operating with treatment and follow-up.
  • Patients can have received bevacizumab prior to trial entry providing that the last dose was administered at least 6 months before the first dose of IMP.

Who cannot join

  • Radiotherapy, surgery or tumour embolisation within 28 days before the first dose of IMP
  • Endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C and six weeks for investigational medicinal products) before the first dose of IMP.
  • Ongoing grade ≥ 2 toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Chief and Principal Investigators should not exclude the patient; and grade 1 or 2 neurotoxicity considered to be due to paclitaxel.
  • Female patients who are able to become pregnant (or are already pregnant or lactating). Those who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
  • Major thoracic or abdominal surgery from which the patient has not yet recovered.
  • At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
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  • Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  • History of any of the following cardiovascular conditions within the last six months:
  • Coronary revascularisation (percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG))
  • Acute coronary syndrome (myocardial infarction (MI), unstable angina)
  • Symptomatic peripheral vascular disease
  • Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (Appendix 4)
  • Patients who have sustained hypertension, defined as a systolic blood pressure (SBP) of > 140 mm Hg or diastolic blood pressure (DBP) of > 90 mm Hg, on three occasions.
  • ECG with evidence of clinically significant abnormalities.
  • Patients with a QTc> 480ms or taking any drug known to prolong the QTc interval that cannot be stopped for the duration of the trial (Appendix 4).
  • Patients with pathologic bradycardia (<60 b/m in non-athletes), heart block (excluding first-degree block, being PR interval prolongation only).
  • History of cerebrovascular accident (including transient ischaemic attack (TIA)), pulmonary embolism or untreated deep vein thrombosis (DVT) within the past six months. Patients with recent DVT or pulmonary embolism who have been treated with therapeutic anti-coagulant agents for at least six weeks will be eligible, provided their INR (if taking oral anti-coagulants) has been stable for this period of time.
  • History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously treated CNS metastases, are asymptomatic and have had no requirement for steroids or anti-convulsant medication for six months prior to the first dose of IMP.
  • Clinically significant abnormalities that may increase the risk of gastrointestinal bleeding or perforation, including but not limited to:
  • Bleeding: Active peptic ulcer disease, known intraluminal metastatic lesions with risk of bleeding, Inflammatory bowel disease (Crohn's disease, ulcerative colitis);
  • Perforation: History of abdominal fistula or large pelvic mass; gastrointestinal perforation or intra-abdominal abscess within four weeks prior to first dose of IMP; previous bowel surgery which is judged by the investigator to increase significantly the risk of gastrointestinal complications from trial treatment
  • Evidence of active bleeding or bleeding diathesis.
  • Transfusion within one week prior to first dose of IMP.
  • Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
  • Clinically significant haemoptysis, within eight weeks before the first dose of IMP.
  • Previous treatment with pazopanib.
  • Any participant that is participating in (or plans to participate in) another interventional clinical trial, whilst taking part in this Phase Ib/II study of fosbretabulin and pazopanib. Participation in an observational trial would be acceptable.
  • Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  • Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy for at least 2 years.
  • Hypersensitivity to Pazopanib or any of it's excipients

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

United Kingdom10 sites

  • Royal United Hospital Bath NHS Trust

    Bath, BA1 3NG

  • City Hospital

    Birmingham, B18 7GH

  • University Hospitals Bristol NHS Foundation Trust

    Bristol, BS1 3NU

  • University Collage London Hospitals NHS Foundation Trust

    London, NW1 2PG

  • The Royal Marsden NHS Foundation Trust

    London, SM2 5PT

  • The Christie NHS Foundation Trust

    Manchester, M20 4BX

  • Clatterbridge Centre for Oncology NHS Foundation Trust

    Metropolitan Borough of Wirral, CH63 4JY

  • Mount Vernon Cancer Centre (East and North Herts NHS Trust)

    Middlesex, HA6 2RN

  • Freeman Hospital (Newcastle-upon-Tyne Hospitals NHS Foundation Trust)

    Newcastle upon Tyne, NE7 7DN

  • Oxford Radcliffe Hospitals NHS Trust

    Oxford, OX3 9DU

Other trials in United Kingdom

About this study

Official title: A Phase Ib and Randomised Phase II Trial of Pazopanib With or Without Fosbretabulin in Advanced Recurrent Ovarian Cancer

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.

Read the detailed description

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.

Being tested
Pazopanib, Fosbretabulin
Keywords
Advanced Recurrent Ovarian Cancer, Pazopanib, Votrient, Fosbretabulin
Medical subject headings
Ovarian Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PazopanibDrug

    Also called Votrient, EU/1/10/628/001, EU/1/10/628/002

    Tyrosine Kinase Inhibitor

  • FosbretabulinDrug

    Also called Fosbretabulin tromethamine

    Vascular Disrupting Agent

Study groups in NCT02055690
Study groupRoleWhat they receive
Phase Ib/II: Fosbretabulin & PazopanibExperimentalPhase Ib: Fosbretabulin and Pazopanib in combination. 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 until disease progression. Pazopanib will be either 600 mg or 800mg taken orally each day of 28 day cycle until disease progression. The phase II dose of both drugs will be determined by the Phase Ib component which is a dose finding exercise. Phase II: Fosbretabulin and Pazopanib in combination. Fosbretabulin 54mg/m2 delivered by infusion every week for 3 weeks of a 4 week for 28 day cycle until disease progression. Pazopanib 600mg taken orally each day for 28 day cycle until disease progression
Receives: Drug: Pazopanib; Drug: Fosbretabulin
Phase II: PazopanibActive comparatorPazopanib 800mg taken orally each day of 28 day cycle until disease progression
Receives: Drug: Pazopanib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase Ib: Dose Limiting Toxicities of Dose of Pazopanib and Fosbretabulin

    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

    Measured: 4 weeks after starting treatment (1 cycle)

  2. Phase II: Progressive disease

    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).

    Measured: Progressive disease (average of 4 months from start of treatment) measured by RECIST

Secondary outcomes (5)

  1. Phase I: Biomarker changes on a cohort-by cohort basis

    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

    Measured: 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)

  2. Phase Ib and Phase II: Safety and Toxicity profile of Pazopanib and Fosbretabulin in combination

    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.

    Measured: 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)

  3. Phase II: Biomarker signature for Progression Free Survival

    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

    Measured: Samples taken within the 4 weeks prior to first dose of drug

  4. Phase II: Response rates by RECIST and GCIG CA-125 criteria

    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

    Measured: Progressive disease (average of 4 months from start of treatment) measured by RECIST and CA125 biomarkers

  5. Phase II: Biomarker response in combination arm

    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.

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Feb 2014 (estimated)
  2. Study startSep 2014
  3. Primary completion24 Nov 2017
  4. Study completion24 Nov 2017

Why it stopped: Safety

Resources

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 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
21 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02055690
Sponsor's protocol ID
13_DOG01_119
Other IDs
2013-005471-40
Acronym
PAZOFOS
Status last verified
May 2021
First submitted
2 Feb 2014
Last updated
17 May 2021
Results posted
No
Data monitoring committee
Yes

Publications

  • Morgan RD, Banerjee S, Hall M, Clamp AR, Zhou C, Hasan J, Orbegoso C, Taylor S, Tugwood J, Lyon AR, Dive C, Rustin GJS, Jayson GC. Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. Gynecol Oncol. 2020 Mar;156(3):545-551. doi: 10.1016/j.ygyno.2020.01.005. Epub 2020 Jan 10.

    PubMed 31932108

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Pazopanib and Fosbretabulin in people with Ovarian Neoplasms and Neoplasms, Ovarian, run by The Christie NHS Foundation Trust at 10 sites in United Kingdom.

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 20 inclusion and 30 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: stopped early, as of the sponsor's last update on 17 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in United Kingdom. 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 combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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?

The study was stopped early (reason given: Safety). Results are not available in the source record.

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?

Phase Ib: Dose Limiting Toxicities of Dose of Pazopanib and Fosbretabulin (time frame: 4 weeks after starting treatment (1 cycle)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02055690, which also lists 1 linked publication.

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 17 May 2021.

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