| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic breast or ovarian carcinoma (proven carrier of a mutation in BRCA1 or 2 gene) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast and ovarian cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
1) To determine whether AG-014699 has antitumour activity in locally advanced or metastatic breast and advanced ovarian cancer shown to express the BRCA 1 or 2 mutations
2) To evaulate the toxicity of treatment with AG-014699 in these populations. |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the time to progression and overall survival after treatment with AG-014699
2) To study pharmacokinetics of AG-014699 in these patient populations
3) To evaluate the PARP activity in peripheral blood lymphocytes from BRCA 1 and 2 heterozygotic patients
4) To determine a safe and effective dosing regimen for AG-014699 oral formulation. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All stages of the study (IV and oral):
1) Patients must be proven known carriers of a mutation of BRCA1 or BRCA2 or considered to be highly likely to be carriers of a BRCA1 or 2 mutation* (score of > 20 as per Manchester criteria) and have histologically documented locally advanced or metastatic breast cancer or advanced ovarian cancer.
*Patients considered highly likely to be carriers will be tested after consenting and a BRCA1 or 2 mutation must be confirmed for the patient to be eligible to receive treatment.
Oral stage 1 only:
In addition to the above, patients with high grade serous ovarian cancer with unknown BRCA status may be entered into oral stage 1.
2. Patients with ovarian cancer (including epithelial, fallopian tube cancer and primary peritoneal cancer) who have had no more than 5 prior chemotherapy regimens in the last 5 years. For the BRCA carriers > 2 months must have elapsed since their last treatment with a carboplatin-or cisplatin-containing regimen or for high grade serous ovarian cancer patients ≥ 6 months.
3) Patients with breast cancer who have had no more than 5 prior chemotherapy regimens in the last 5 years.
4) Measurable disease as measured by X-ray, computerised tomography (CT) or MRI scan as defined by RECIST criteria. These measurements must be done within 3 weeks of the patient going on study. The interval between the last anti-cancer therapy and these measurements must be at least 4 weeks. Clinical measurements must be done within one week of the patient going on study. Patients with bone disease must have other measurable disease for evaluation.
5) Life expectancy of at least 12 weeks.
6) World Health Organisation (WHO) performance status of 0 or 1.
7) Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week before the patient goes on study.
Lab Test Value required
Haemoglobin (Hb) ≥9.0 g/dl
Neutrophils ≥1.5 x 109/L
Platelets (Plts) ≥100 x 109/L
Serum bilirubin ≤1.5 x upper normal limit
ALT and/or AST ≤ 2.5 x ULN unless due to tumour when up to 5 x ULN is allowed
Glomerular Filtration Rate (GFR) ≥50 ml/min
calculated by the Wright formula
(see Appendix 5) or Cockcroft-Gault formula
or by isotope clearance measurement
8) 18 years or over
9) Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up |
|
| E.4 | Principal exclusion criteria |
1) Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy, biological agents, or investigational agents during the previous four weeks (six weeks for nitrosoureas and Mitomycin-C) before treatment.
2) The administration of strong CYP1A2 or CYP3A4 inhibitors/inducers (for example, but not limited to; ciprofloaxacin and ketoconazole): within 1 week before treatment, unless a specific exception is agreed upon in writing prior to patient entry between the Principal Investigator and CR-UK Medical Advisor.
3) Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the Drug Development Office (DDO) should not exclude the patient.
4) Known brain metastases.
5) Female patients able to become pregnant (or already pregnant or lactating). However, those female patients 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 intrauterine device and condom, diaphragm with spermicidal gel and condom, or are surgically sterilised) 4 weeks before entering the trial, during the trial and for 6 months afterwards are considered eligible.
6) Male patients with partners of child-bearing potential (unless they agree to use one form of highly effective contraception such as a barrier method of condom plus spermicide during the trial and for six months afterwards).
7) Major thoracic and/or abdominal surgery in the preceding four weeks from which the patient has not recovered.
8) At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
9) Concurrent malignancies at other sites, 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 concurrent breast and ovarian carcinoma. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, are eligible for the study.
10) Patients with active or unstable cardiac disease or history of myocardial infarction within 6 months. Patients with cardiovascular signs or symptoms should have a MUGA scan or echocardiogram, and those patients with left ventricular ejection fraction below the institutional limit of normal should be excluded.
11) Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial.
12) Patients who have already received a PARP inhibitor |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Assessment of antitumour activity according to RECIST will be made using tumour size measured clinically or radiologically with coaxial tomography (CT), magnetic resonance imaging (MRI), plain x-ray, or other imaging techniques.
2) Safety profile of AG-014699 in these populations. Any adverse event will be fully characterized and evaluated for causality according to CTCAE criteria version 3.0
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Within 4 weeks. Pretreatment, every 2 cycles.
2) From start of treatment to 28 days after last dose. |
|
| E.5.2 | Secondary end point(s) |
1) Time to progression and overall survival after treatment with AG-014699
2) Plasma levels of AG-014447 (the active drug of prodrug AG-014699) in these populations will be measured using Liquid Chromatography/Mass Spectrometry/Mass Spectrometry (LC/MS/MS)
3) PARP activity will be measured ex vivo using validated assays.
4) Assessment of antitumour activity and the safety profile of AG-014699, as described above, will be used to determine the oral optimal dosing regimen. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Progression-followed quarterly until disease progression
Survival-1 year after off-study visit for each patient
2) During cycles 1 and 2 of treatment for all patients
3) During cycle 1 of treatment for all patients
4) Antitumour activity-as per primary end point 1
Safety-as per primary end point 2 |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 10 |
| 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 | Information not present in EudraCT |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The ‘end of trial’ is defined as the date when the last patient has been followed up for survival either 1 year after the off-study visit or until further treatment or death is known (whichever is earlier). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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