| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Tumores sólidos avanzados, cáncer de mama triple negativo
Advanced Solid Tumours, Triple Negative Breast Cancer |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
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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 |
Primary objective:
· Part A/Phase I: The primary objective is to determine the safety and tolerability of twice daily oral doses of AZD2281 when administered in combination with cisplatin to patients with advanced solid tumours.
· Part B/Phase II: The primary objective is to assess the complete pathological response rates of AZD2281+ cisplatin versus cisplatin alone in the treatment of patients with Triple Negative Breast Cancer in the neoadjuvant setting.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
1. To compare exposure to AZD2281 when given alone and in combination with cisplatin. (Part A/Phase I).
2. To study the safety and tolerability of AZD2281 in combination with cisplatin in patients with Triple Negative Breast Cancer suitable for curative intent surgery in the neoadjuvant phase. (Part B/Phase II).
3. To make a preliminary assessment of the anti-tumour activity of AZD2281 when given in combination with cisplatin, by measuring overall response rate (Part A and B)
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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 |
Title of the genetic substudy:
"A Phase I/II, Open Label, Multi-centre Study of AZD2281 Administered Orally in Combination with Cisplatin, to Assess the Safety and Tolerability in Patients with Advanced Solid Tumours, and to Assess Efficacy in the Neoadjuvant Setting for Patients with Triple Negative Breast Cancer"
Date of the genetic substudy: 07 July 2008
Version of the genetic substudy: 1
Objectives: To obtain an optional blood sample for DNA extraction for future pharmacogenetic analysis and other potential correlative markers of the activity of AZD2281 and drugs taken in combination with AZD2281 |
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| E.3 | Principal inclusion criteria |
For inclusion in the study subjects must fulfil all of the following criteria:
1. Fully-informed written consent.
2. Adequate bone marrow, hepatic and renal function including the following:
- Haemoglobin ≥9.0 g/dL
- White blood cell count >3 x 109/L
- Absolute neutrophil count ≥1.5 x 109/L
- Platelets ≥100 x 109/L;
- Total bilirubin ≤1.5 x upper normal limit;
- AST (SGOT), ALT (SGPT) ≤2.5 x upper normal limit (or ≤5x UNL in the presence of liver metastases);
- Serum creatinine ≤1.5 mg/dL
- Creatinine Clearance >50mL/min
3. Male or female patients, age ≥18 years.
4. Performance status (PS) ≤2 (ECOG scale).
5. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
6. Negative pregnancy test for women of childbearing potential only
Phase I specific inclusion criteria:
7. Histologically confirmed metastatic cancer, not amenable to surgery or radiation therapy with curative intent.
8. Life expectancy of at least 12 weeks.
9. Patients with measurable or non measurable disease according to RECIST (see Appendix G)
Phase II specific inclusion criteria:
10. All tumours must be ER-, PR- and HER-2 negative (HER-2 0,1+ by IHC; HER-2 2+ must be negative by FISH).
11. Patients with measurable disease on MRI according to appendix G
12. Breast cancer Stage Clinical T 2-3, N0 1, M0.
- Patients with stage II or III breast cancer are eligible. This includes T2-3, N0 1, and M0. Cancer in the breast and/or axilla must be equal or greater than 2.0 cm.
NB Patients with a HER2 negative ipsilateral breast recurrence are NOT eligible unless prior treatment consisted of excision alone for DCIS or breast conserving treatment and hormonal therapy for DCIS or invasive cancer.
For inclusion in the genetic component of the study, subjects must fulfil the following criterion:
· Provision of informed consent for genetic research
If a subject declines to participate in the pharmacogenetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent.
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| E.4 | Principal exclusion criteria |
Any of the following is regarded as a criterion for exclusion from the study:
1. Major surgery within 4 weeks of starting the study.
2. Co-existing active infection.
3. Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel obstruction, malabsorption) or with the patient’s ability to take regular oral medication.
4. Patients requiring treatment with inhibitors or inducers of CYP3A4.
5. Patients currently experiencing seizures or who were currently being treated with any anti-epileptic for seizures (use of anti-epileptic drugs to control pain is allowed in patients not suffering from seizures unless drug is excluded due to CYP3A4 induction – phenytoin, carbamazapine, phenobarbitone.
6. Patients who are unable to swallow oral medication.
7. A positive pregnancy test. Pregnant or breast-feeding women or women of childbearing potential unless effective methods of contraception are used (lack of childbearing potential is met by being post-menopausal, being surgical sterile, practicing contraception with an oral contraceptive or other hormonal therapy [eg, hormone implants], intra-uterine device, diaphragm with spermicide or condom with spermicide, or being sexually inactive. Patients and their partners must agree to use one of the above forms of contraception throughout the treatment period and for 3 months after discontinuation of treatment.
8. Renal dysfunction for which exposure to cisplatin would require dose modification or be completely unsafe (serum creatinine >1.5 mg/dL)
9. Immunocompromised patients e.g. Patients who are known to be serologically positive for human immunodeficiency virus (HIV).
10. Patients with active or severe cardiovascular or pulmonary disease, including recent (<6 months) myocardial infarction or deep-venous thrombosis/pulmonary embolism, congestive heart failure, uncontrolled hypertension (systolic blood pressure >180 mm Hg, diastolic blood pressure >105 mm Hg), or steroid-dependent asthma, are ineligible.
11. Patients with peripheral neuropathy of any etiology that exceeds grade 1 are ineligible.
12. Patients with uncontrolled diabetes (fasting blood sugar >200 mg/dL) are ineligible.
13. Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study e.g. patients with a clinically significant hearing impairment..
14. Simultaneous participation in any other study involving an investigational medicinal product, or having participated in a study less than 28 days prior to the start of study treatment.
15. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
16. Known hypersensitivity to AZD2281 or any of its excipients, cisplatin or other platinum containing compounds
17. Use of live virus vaccinations within 3 months before or after treatment
Phase I specific exclusion criteria:
18.Less than 28 days from active therapy (i.e. any treatment used to treat the disease) or high dose radiotherapy (patients may continue concomitant use of a stable dose of bisphosphonates if used for at least 28 days prior to commencing study treatment and patients may receive palliative radiotherapy for bone disease during the study)
19.Brain metastases or spinal cord compression, unless irradiated at least 4 weeks before entry and stable without steroid treatment for ≥ 1 week.
20.Persistent CTCAE grade 2 or greater toxicities (excluding alopecia) caused by prior therapy
Phase II specific exclusion criteria:
21.Any prior chemotherapy or radiotherapy.
22.Patients must not have any other pre-existing medical condition that would represent toxicity in excess of grade 1 as measured by the NCI criteria.
23.Patients with a prior history of malignancy treated without curative intent.
24.Evidence of metastatic disease
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical endpoints (Phase II):
Objective response rate:
The primary objective of the Phase II part of the study is to compare complete pathological response rates between the 2 treatment groups.
Surgical breast and axillary node resection specimens will be evaluated for pathologic tumour response according to NSABP guidelines (Fisher et al 2002). Patients will be considered in pCR if no invasive cancer or only in-situ cancer is observed in the breast specimen. The above system does not take into account the nodal status to define pCR. The Miller-Payne pathologic system will be use to code response. All study samples will be reviewed by two breast pathologists expert in the Miller-Payne system to provide codes for response analysis (Part B/Phase II only).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | 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) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| 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 | 2 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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
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| The end of the study is defined as when the database lock is performed and no patients are receiving ongoing treatment with AZD2281. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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