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

NCT02055690 | Terminated Phase 1 DMC

• 2 other identifiers: 13_DOG01_1192013-005471-40
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 10

Brief 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. 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.

Conditions

Ovarian Neoplasms; Neoplasms, Ovarian; Ovarian Cancer

Keywords

Advanced Recurrent Ovarian Cancer; Pazopanib; Votrient; Fosbretabulin

Outcome Measures

Primary Outcomes (2)

• 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

  4 weeks after starting treatment (1 cycle)

• 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).

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

Secondary Outcomes (5)

• Phase I: Biomarker changes on a cohort-by cohort basis

  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)

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

  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)

• Phase II: Biomarker signature for Progression Free Survival

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

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

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

• Phase II: Biomarker response in combination arm

  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)

Study Arms (2)

Phase Ib/II: Fosbretabulin & Pazopanib

EXPERIMENTAL

Phase 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

Drug: Pazopanib; Drug: Fosbretabulin

Phase II: Pazopanib

ACTIVE COMPARATOR

Pazopanib 800mg taken orally each day of 28 day cycle until disease progression

Drug: Pazopanib

Interventions

Pazopanib DRUG

Tyrosine Kinase Inhibitor

Also known as: Votrient, EU/1/10/628/001, EU/1/10/628/002

Phase II: Pazopanib; Phase Ib/II: Fosbretabulin & Pazopanib

Fosbretabulin DRUG

Vascular Disrupting Agent

Also known as: Fosbretabulin tromethamine

Phase Ib/II: Fosbretabulin & Pazopanib

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• The Christie NHS Foundation Trust: lead
• Novartis: collaborator
• Mateon Therapeutics: collaborator
• East and North Hertfordshire NHS Trust: collaborator

Study Sites (10)

Royal United Hospital Bath NHS Trust

Bath, BA1 3NG, United Kingdom

Location

City Hospital

Birmingham, B18 7GH, United Kingdom

Location

University Hospitals Bristol NHS Foundation Trust

Bristol, BS1 3NU, United Kingdom

Location

University Collage London Hospitals NHS Foundation Trust

London, NW1 2PG, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, SM2 5PT, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Clatterbridge Centre for Oncology NHS Foundation Trust

Metropolitan Borough of Wirral, CH63 4JY, United Kingdom

Location

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

Middlesex, HA6 2RN, United Kingdom

Location

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

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Oxford Radcliffe Hospitals NHS Trust

Oxford, OX3 9DU, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 31932108 DERIVED

Related Links

• Christie NHS website

MeSH Terms

Conditions

Ovarian Neoplasms

Interventions

pazopanib; fosbretabulin

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Gordon Jayson

  The Christie National Health Service (NHS) Foundation Trust

  STUDY CHAIR

• Gordon Rustin

  East and North Herts NHS Trust

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2014
• First Posted: February 5, 2014
• Study Start: September 1, 2014
• Primary Completion: November 24, 2017
• Study Completion: November 24, 2017
• Last Updated: May 17, 2021

Record last verified: 2021-05

Locations

GB (10)