| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with metastatic breast cancer in 1st or 2nd line of chemotherapy |
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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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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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 evaluate whether treatment with targeted agents guided by high throughput molecular analyses (CGH array, next generation sequencing) improves overall progression-free survival as compared to standard maintenance chemotherapy in patients with metastatic breast cancer. |
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| E.2.2 | Secondary objectives of the trial |
- To compare overall survival
- To evaluate overall response rates and change in tumor size
- To evaluate safety,
- To explore the efficacy (response rate, change in tumor size, progression-free survival, overall survival) of the individual targeted agents,
- To investigate the efficacy (response rate, change in tumor size, progression-free survival, overall survival) according to the order of preference for treatment.
- To correlate molecular mechanisms in patients with the efficacy endpoints (response rate, progression-free and overall survival)
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The following, but not limited, research program is under the supervision of the steering committee which role is to consider how the projects should be modified in their objectives or in the technics they use, or even if they are still relevant in regards to the current state of scientific knowledge.
1/ Circulating tumor DNA analysis to investigate:
a/ correlation of ctDNA profiles with those obtained with NGS in the tumor sample;
b/ identification of molecular alterations linked to resistance to targeted therapies.
2/ Validation of the functional protein activation and exploration of the sequence of events in the signalling pathways, using FISH and CISH, IHC staining, kinome arrays and RPPA analysis.
3/ Investigation of molecular changes that underlie disease progression and the formation of metastases
a/ using whole exome sequencing program on normal cellsand metastatic tumor material;
b / comparing the variation on molecular profiles from different metastatic sites
4/ Construction of a virtual cell to develop the optimal algorithm able to identify the driver alterations and then to deliver the optimal choice of therapy.
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| E.3 | Principal inclusion criteria |
1. Patients who received 6 to 8 cycles of chemotherapy, or having received at least 4 cycles of chemotherapy stopped for toxicity reasons, and who are presenting a stable or a responding disease at the time of randomization
2. Patients who still meet the screening phase inclusion criteria and exclusion criteria
3. Patients whose tumor sample is presenting at least one genomic alteration from the list of predefined targetable genomic alterations and for whom the multidisciplinary tumor board has provided a personalized guidance.
4. Age ≥ 25 years for patients planned to receive AZD4547
5. Patients will have had at least a 28-day wash-out period from last chemotherapy administration prior to randomization and should have recover (grade ≤1) from all residual toxicities, excluding alopecia.
6. Potentially reproductive patients must agree to use an effective contraceptive method or practice adequate methods of birth control or practice complete abstinence while on treatment, beginning 2 weeks before the first dose of investigational product and for at least 3 months after the last dose of study drug.
7. Women of childbearing potential must have a negative serum pregnancy test done within 14 days of enrollment and/or urine pregnancy test 72 hours prior to the administration of the study drug.
8. Women who are breastfeeding should discontinue nursing prior to the first dose of study drug and until 3 months after the last dose.
9. Provision of signed and dated, written informed consent prior to randomization and to any study specific procedures, sampling and analysis
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| E.4 | Principal exclusion criteria |
1. No “targetable” genomic alteration identified during the screening phase (either due to the lack of alteration or due to ineligible samples for genomic analysis) or unfavorable decision from the multidisciplinary tumor board to drive the patient to the randomization.
2. More than 2 previous lines of chemotherapy for metastatic disease before randomization
3. Life expectancy < 3 months
4. Disease progression occuring at any time during chemotherapy and before randomization or toxicity that led to the discontinuation of the last chemotherapy before 4 full cycles have been delivered
5. Major surgery within 30 days (excluding placement of vascular access) or minor surgery within 14 days prior to randomisation
6. Less than 28 days from radiotherapy (wide field of radiation), less than 2 weeks from palliative radiation (limited fields). Fields should not have involved all target lesions
7. Patients treated in the last 30 days with a targeted agent in the same class as agents tested in this study
8. Participation to another clinical study with an investigational product (IP) during the last 30 days
9. History of hypersensitivity to active or inactive excipients of the study drug
10. Toxicities of grade ≥2 from any previous anti-cancer therapy, with the exception of alopecia
11. Altered haematopoietic or organ function, as indicated by the following criteria:
- Polynuclear neutrophils < 1.5 x 10^9/L
- Platelets < 100 x 10^9/L
- Haemoglobin < 90 g/L
- ALAT/ASAT > 2.5x ULN in the absence of or > 5x ULN in the presence of liver metastases
- bilirubin > 1.5xULN
- creatinine clearance ≤50 mL/min (measured or calculated by Cockroft and Gault formula)
- Proteinuria > 3+ on dipstick analysis or > 3.5g/24 hours or a urine protein/creatinine ratio > 3.5 (only for patients drived to receive AZD5363)
- Sodium, magnesium, calcium and phosphate > ULN
- Potassium < 4 mmol/L
- glycosylated haemoglobin (HbA1C) ≥ 8.0% (64 mmol/mol), (only for patients supposed to receive AZD5363)
- Fasting Plasma Glucose ≥ 7.0 mmol/L(126 mg/dL) (fasting is defined as no calorie intake for at least 8 hours)
12. Any of the following additional cardiac criteria:
- Mean resting corrected QT interval (QTc)>480msec (or QTcF >450 msec) obtained from 3 consecutive ECGs
- LVEF <55% (MUGA scan or Echocardiogram).
13. Altered ophthalmic conditions confirmed by an ophthalmology specialist for patients likely to be treated with :
- AZD4547 : current evidence or previous history of retinal pigmented epithelium detachment (RPED), previous laser treatment or intra-ocular injection for treatment of macular degeneration, current evidence or previous history of dry or wet age-related macular degeneration, current evidence or previous history of retinal vein occlusion (RVO), current evidence or previous history of retinal degenerative diseases (eg, hereditary), current evidence or previous history of any other clinically relevant chorioretinal defect
- AZD8931 : any eye injury in the previous 3 months or a prior eye injury still associated with persistent or recurrent symptoms or impairment of vision, corneal surgery (laser refractive surgery performed more than 3 months prior to the start of the trial is allowed and should be recorded in surgical history), orbital irradiation, collagen vascular, chronic inflammatory or degenerative disease with eye involvement (eg, rheumatoid, Sjögren’s syndrome, systemic lupus erythematosus [SLE]), clinically significant ocular surface disease i.e. diseases of the conjunctiva and cornea (including atopic keratoconjunctivitis, Stevens Johnson syndrome, ocular cicatricial pemphigoid or chemical burns, Herpes simplex or Herpes zoster virus eye disease), evidence of maculopathy in patients with impaired visual acuity (impaired visual acuity is defined as best corrected near visual acuity <0.4 or best corrected distance visual acuity (including with pinhole) <0.7).
- Selumetinib : intraoccular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intraocular pressure), current or past history of central serous retinopathy or retinal vein occlusion
14. Patients using drugs that are known potent inhibitors or potent inducers or substrates of cytochrome P450 are not eligible if those treatments cannot be substituted from 14 days prior to the first dose (except those for which the minimum wash-out period is longer, e.g. Fluoxetine and Phenobarbital: 5 weeks, Rifabutin : 3 weeks and amiodarone: 27 weeks) and during the study.
15. Patients using non-substitutable drugs, that are known to prolong QT interval or induce Torsades de Pointes, from 14 days prior to the first dose (except those for which the minimum wash-out period is longer) and during the study, are not eligible when they are supposed to be treated with vandetanib, AZD5363 or AZD8931
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Anti-tumor activity of all the agents, as the primary objective of the trial, will be carried out by the determination of the progression-free survival assessed in each arm of treatment.
Progression-free survival (PFS) is defined as the time from randomization to the first documented progression of disease or death, whatever the cause. The tumor assessments are made by the investigators based on RECIST 1.1 criteria ([Eisenhauer 2009]). Patients still alive at the time of analysis without documented progression (including lost to follow-up) will be censored at the last known alive date.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Overall Survival :
Overall Survival (OS) is defined as the time from randomization to death due to any cause. Patients still alive at the time of analysis (including lost to follow-up) will be censored at the last known alive date.
Response and change in tumor size :
Objective response (i.e. complete or partial response) will be defined using RECIST V1.1 criteria.
Changes in tumor size over time will also be analysed.
Safety :
Evaluation of safety will be done according to NCI CTCAE v4.03 criteria.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| chemotherapy administered without considering the tumour genome analysis |
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| 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 | 18 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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