| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| 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 | 20.0 |
| 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 | 20.0 |
| 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 |
To investigate whether the addition of a novel agent to weekly paclitaxel improves efficacy (how well treatment works), compared with paclitaxel plus placebo, in patients with relapsed platinum-resistant ovarian cancer.
The progression free survival (the length of time during and after cancer treatment that a patient lives with the disease but it does not get worse) will be compared. |
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| E.2.2 | Secondary objectives of the trial |
1. To assess and compare the tumour response (shrinkage, growth) following paclitaxel chemotherapy (standard care) plus placebo and the combination of paclitaxel plus a novel agent
2. To assess and compare the length of patient survival
3. To determine the side effects and safety of the combination of paclitaxel plus a novel agent
4. To assess the impact of treatment on quality of life
5. To assess use of resource within the NHS
6. To explore predictive biomarkers of response (identify which patients most likely to benefit from treatment) to a novel agent with paclitaxel and paclitaxel alone
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
INCLUSION CRITERIA (GENERIC)
1. Age ≥ 18 years
2. Histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer (please note that patients who have an original diagnosis based on cytology only will not be eligible for entry into the study unless a biopsy confirming high grade serous histology is performed). Please note that Grade 3 serous on pathology reports are accepted as high grade serous. Any patient originally diagnosed with a ‘grade 2 serous’ pathology must undergo pathology review to confirm high grade pathology.
3. Platinum-resistant disease defined as progression within 6 months of completing prior platinum therapy. This includes platinum-refractory disease. Progression is defined by RECIST criteria v1.1 (radiologically with measurable disease), but patients with CA125 progression (GCIG CA125 Criteria) plus symptoms indicative of progression will also be allowed to enter.
4. Measurable or evaluable disease (if not measurable by RECIST criteria v1.1, must be evaluable by GCIG CA125 criteria). Patients with CA125 progression in the absence of symptoms will NOT be eligible.
5. Histological tissue specimen available (tissue block or 8-10 unstained slides) must be available (specimen can be the sample at diagnosis or taken at relapse). Otherwise, a biopsy must be carried out to obtain sufficient tissue for histological assessment.
6. Willingness to undergo mandatory biopsy pre cycle 1 day 1. Target lesions (RECIST criteria v1.1) should be avoided if possible.
7. Prior taxane use: Patients whom have received prior 3 weekly paclitaxel (or other 3 weekly taxane) are permitted. Patients whom received weekly paclitaxel as part of first line treatment in combination with platinum are eligible if the interval since the last dose of weekly paclitaxel is > 6months at the time of randomisation. Patients whom received prior weekly paclitaxel (alone or in combination) for platinum-resistant disease are excluded. If patients have received prior taxane, the interval since the last taxane treatment must be known. The treatment immediately prior to study entry need not be platinum-based. Entry into the trial is not limited to first line treatment for platinum-resistant ovarian cancer ie. patients can have prior lines of therapy for platinum-resistant disease.
8. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed
9. Adequate haematological and biochemical function as indicated below. These measurements must be performed within 7 days prior to randomisation:
• Absolute neutrophil count ≥1.5 x 109/L
• Platelet count ≥100 x 109/L
• Haemoglobin ≥90 g/L
• Serum creatinine <1.5 times ULN or creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation/Wright formula); confirmation of creatinine clearance is only required when serum creatinine is ≥1.5 times the ULN
• Total bilirubin <1.5 times ULN. In cases of Gilbert’s syndrome, bilirubin < 2 x ULN is allowed
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or <5 times ULN in the presence of liver metastases
• Alkaline phosphatase <5 x ULN
10. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other study procedures
11. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days of trial treatment
a. Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years old who have been amenorrhoeaic for at least 12 months following cessation of all exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the post-menopausal range for the institution
OR
b. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
12. Patients with synchronous tumours e.g. ovarian and endometrial or history of prior malignancy are eligible provided that there is biopsy evidence that the disease measurable on CT and/or MRI is ovarian in origin.
13. Life expectancy of at least 12 weeks
14. ECOG Performance Status of 0,1
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| E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA (GENERIC)
1. Non high grade serous histologies including carcinosarcoma.
2. Prior chemotherapy, biological therapy, radiation therapy, hormonal anti-cancer therapy, immunotherapy, other anticancer agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites). Treatment with any investigational agent within the preceding 4 weeks or within 5 half-lives of the investigational agent, whichever is longer.
3. Pregnant or lactating women
4. Women of childbearing age and potential who are not willing to use two highly effective forms of contraception as detailed Pregnancy section. In addition, patients will be excluded if they are not willing to use contraception for the duration as documented in Pregnancy Sections.
5. With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.03) Grade 1 at the time of starting study treatment.
6. Major surgery within 4 weeks prior to entry to the study or minor surgery within 2 weeks of entry into the study (excluding placement of vascular access)
7. Spinal cord compression, known leptomeningeal involvement or brain metastases, unless treated and stable off steroids for at least 4 weeks prior to randomisation
8. Oral anticoagulants such as warfarin are not permitted, with the exception of 1mg daily warfarin dose for the prevention of hickman line clotting. Anticoagulation with low molecular weight heparin is allowed.
9. Any haemopoietic growth factors (e.g., G-CSF, GM-CSF) and blood transfusions within 2 weeks prior to randomisation
10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease], uncontrolled chronic renal diseases (glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis), current unstable or uncompensated respiratory or cardiac conditions, uncontrolled hypertension, active bleeding diatheses or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required.
11. Torsades de Pointes within 12 months of study entry
12. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements
13. Patients with a history of grade 3 or 4 allergic reaction (CTCAEv4.03) to paclitaxel are not permitted. Patients who have had prior grade 1 or 2 hypersensitivity reactions are permitted providing the weekly paclitaxel is administered using the desensitisation schedule (section 5.7.2).
14. Patients who have a new diagnosis of deep vein thrombosis or pulmonary embolism within 2 weeks of randomisation are permitted if clinically stable on a therapeutic dose of LMWH. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for this study is progression free survival (PFS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Radiological and CA125 assessment of disease will take place every 8 weeks whilst patients are on study. |
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| E.5.2 | Secondary end point(s) |
The secondary end points are as follows:
1. Response (based on RECIST 1.1 and GCIG CA125 Criteria)
2. Overall Survival
3. Safety and Tolerability
4. QoL as measured by EQ-5D
5. Resource use for health economics |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Radiological and CA125 assessment of disease response will take place every 8 weeks
2. Patients will be followed up whilst on treatment and off study for overall survival
3. Safety and tolerability will be assessed d1, d8 and d15 during every treatment cycle, d1 during the maintenance period and at the end of study visit
4. EQ-5D QoL will be performed prior to each cycle of paclitaxel +/- novel agent
5. Resource use data will be collected prior to each cycle of paclitaxel +/- novel agent and novel agent along on the maintenance phase |
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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 | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 26 |
| 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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| For the purpose of complying with UK Clinical Trials Regulations introduced in May 2004, the trial will be considered 'closed' when the follow-up point for the primary analysis of the final experimental arm has been reached. However, further observational follow-up of all patients enrolled in the trial will continue until all randomized patients have died. This will initially be via the hospital, but in the longer term may employ national registers. |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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