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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Christie Hospital NHS Foundation Trust
Sponsor:
Collaborators:
GlaxoSmithKline
OXiGENE
East and North Hertfordshire NHS Trust
Information provided by (Responsible Party):
Colin Lunt, Christie Hospital NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT02055690
First received: February 2, 2014
Last updated: October 20, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Ovarian Neoplasms
Neoplasms, Ovarian
Ovarian Cancer
Drug: Pazopanib
Drug: Fosbretabulin
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Christie Hospital NHS Foundation Trust:

Primary Outcome Measures:
  • 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).



Secondary Outcome Measures:
  • 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.



Estimated Enrollment: 128
Study Start Date: September 2014
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

Drug: Pazopanib
Tyrosine Kinase Inhibitor
Other Names:
  • Votrient
  • EU/1/10/628/001
  • EU/1/10/628/002
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
Drug: Pazopanib
Tyrosine Kinase Inhibitor
Other Names:
  • Votrient
  • EU/1/10/628/001
  • EU/1/10/628/002

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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):

    • 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.

Exclusion Criteria:

  • 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.
  • 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 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
  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: NCT02055690

Contacts
Contact: Colin Lunt +44 (0) 161 918 7492 colin.lunt@christie.nhs.uk

Locations
United Kingdom
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         
Sponsors and Collaborators
Colin Lunt
GlaxoSmithKline
OXiGENE
East and North Hertfordshire NHS Trust
Investigators
Study Chair: Gordon Jayson The Christie National Health Service (NHS) Foundation Trust
Study Chair: Gordon Rustin East and North Herts NHS Trust
  More Information

Additional Information:
No publications provided

Responsible Party: Colin Lunt, Clinical Trials Project Manager, Christie Hospital NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02055690     History of Changes
Other Study ID Numbers: 13_DOG01_119, 2013-005471-40
Study First Received: February 2, 2014
Last Updated: October 20, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Christie Hospital NHS Foundation Trust:
Advanced Recurrent Ovarian Cancer
Pazopanib
Votrient
Fosbretabulin

Additional relevant MeSH terms:
Ovarian Neoplasms
Neoplasms
Adnexal Diseases
Endocrine Gland Neoplasms
Endocrine System Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Gonadal Disorders
Neoplasms by Site
Ovarian Diseases
Urogenital Neoplasms
Fosbretabulin
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014