| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| partially platinum resistant ovarian cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057529 |
| E.1.2 | Term | Ovarian cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase Ib (dose escalation) objectives
(a) To propose a recommended dose for Phase II evaluation by: Establishing the maximum tolerated dose of fosbretabulin in combination with pazopanib.
(b) Assessing the safety and toxicity profile of fosbretabulin in combination with pazopanib
Randomised Phase II objectives
To determine whether combining fosbretabulin with pazopanib produces a significant improvement in progression free survival compared to pazopanib alone. |
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| E.2.2 | Secondary objectives of the trial |
Phase Ib (dose escalation) objectives
(a) To define the toxicities of the fosbretabulin in combination with Pazopanib
(b) To define the biomarker changes on a cohort-by cohort basis.
Randomised Phase II objectives
1. The response rate in the pazopanib and combination arms.
2. To investigate whether biomarkers can demonstrate additivity of the combination in comparison with single agent pazopanib
3. To investigate whether the pre-treatment biomarker signature can predict which patients have a response and a longer progression free survival
4. To further assess the safety and toxicity profile of fosbretabulin and pazopanib in combination.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Advanced, progressive, recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma, which has recurred following at least one platinum-containing regimen.
2. 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.
3. World Health Organisation (WHO) performance status of 0 or 1 (Appendix 1).
4. Measurable disease (RECIST 1.1 (Appendix 2) or PD according to CA125 GCIG criteria with non-measurable disease on CT scan.
5. Life expectancy of at least 12 weeks.
6. 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 IMP.
Laboratory Test Value required
Haemoglobin (Hb) ≥ 90 g/L
Absolute neutrophil count ≥ 1.5 x 10*9/L
Platelet count ≥ 100 x 10*9/L
Serum potassium Within normal range
Bilirubin up to 1.5 x ULN and
Alanine aminotransferase (ALT) and/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
Calculated creatinine clearance or isotope clearance measurement ≥ 40 mL/min
Activated partial thromboplastin time (aPTT) ≤ 1.2 x ULN
Prothrombin Time (PT) or International normalised ratio (INR) ≤ 1.3 x ULN
7. Urine protein dipstick of less than 2+, or if 2+ or greater the patient must have a 24 hour urinary protein value of less than 2 g.
8. Clinically euthyroid.
9. Aged 18 years or over at the time of consent.
10. Written (signed and dated) informed consent and capable of co-operating with treatment and follow-up.
11. 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. |
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| E.4 | Principal exclusion criteria |
1. Radiotherapy, surgery or tumour embolisation within 28 days before the first dose of IMP
2. 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.
3. 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.
4. 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.
5. Major thoracic or abdominal surgery from which the patient has not yet recovered.
6. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
7. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
8. History of any of the following cardiovascular conditions within the last six months:
a. Coronary revascularisation (percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG))
b. Acute coronary syndrome (myocardial infarction (MI), unstable angina)
c. Symptomatic peripheral vascular disease
d. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (Appendix 4)
9. 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.
10. ECG with evidence of clinically significant abnormalities.
11. 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).
12. Patients with pathologic bradycardia (<60 b/m in non-athletes), heart block (excluding first-degree block, being PR interval prolongation only).
13. 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.
14. 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.
15. Clinically significant abnormalities that may increase the risk of gastrointestinal bleeding or perforation, including but not limited to:
a. Bleeding: Active peptic ulcer disease, known intraluminal metastatic lesions with risk of bleeding, Inflammatory bowel disease (Crohn’s disease, ulcerative colitis);
b. 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
16. Evidence of active bleeding or bleeding diathesis.
17. Transfusion within one week prior to first dose of IMP.
18. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
19. Clinically significant haemoptysis, within eight weeks before the first dose of IMP.
20. Previous treatment with pazopanib or fosbretabulin.
21. 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.
22. Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial.
23. 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.
24. Hypersensitivity to pazopanib/ fosbretabulin or any of it’s excipients |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For phase Ib the primary outcome measure is to establish the dose of fosbretabulin and pazopanib for the phase II study. This will be done by assessing toxicities to the combination.
For phase II the primary outcome measure is to determine whether the combination of fosbretabulin and pazopanib gives an improvement in progression-free survival (PFS) compared to pazopanib alone. This will be recorded according to CT scans and evaluated using the Response Evaluation Criteria In Solid Tumours (RECIST) 1.1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the primary endpoint for phase I will be after the last patient has had at least one month of treatment and when all data is collected and has been queried. This is expected to take approximately 9 months.
Evaluation of the primary endpoint for phase II will be after the last patient has had their last follow-up visit and all data has been collected and queried. This is expected to take around 36 months. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for phase Ib are to determine the causality of each adverse event according to CTCAE (Common Terminology Criteria for Adverse Events) and to measure VEGFA, VEGFR2, Ang1, Ang2 and Tie 2 biomarkers by ELISA and enumerating circulating tumour cells.
For phase II the secondary endpoints are to determine patient response by RECIST (Response Evaluation Criteria In Solid Tumours)and GCIG (Gynaecologic Cancer Intergroup) CA125 levels and to measure the median progression free survival. Adverse events and biomarkers will also be measured as for phase Ib. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for secondary endpoints will be the same as for the primary endpoints. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase Ib of fosbretabulin+pazopanib followed by randomised phase II of pazopanib vs the combination |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase Ib dose escalation, Phase II randomised |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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