| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone receptor positive primary breast cancer with tumor measuring > 2.0 cm that will be recommended chemotherapy and antihormone therapy according to the treatment guidelines for curative breast cancer treatment. |
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| E.1.1.1 | Medical condition in easily understood language |
| Large breast cancer that will be recommended chemotherapy and antihormonal therapy for treatment with a curative intent. |
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| 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 |
Primary objective - Part 1 (Chemotherapy):
To assess the efficacy of neoadjuvant chemotherapy with or without bevacizumab in a pretreatment selected subgroup, using a molecular signature, in patients with large (cT2 - cT4) hormone receptor positive, HER2 negative breast cancer.
Primary objective - Part 2 (Post chemotherapy)
To assess the effect of capivasertib in combination with letrozole or letrozole alone in patients with hormone receptor positive HER2 negative breast cancer with residual tumor tissue (15 mm or more) in the breast after neoadjuvant therapy. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objective - Part 1 (Chemotherapy) and
econdary objective - Part 2 (Post chemotherapy)
The invasive disease-free survival in the treatment arms. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this clinical study protocol (CSP)
2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
3. Women (or men), age 18 – 80 years, diagnosed with palpable, histologically or cytological confirmed, ER positive (≥1%) HER2-negative, breast adenocarcinoma with a measurable disease (>20 mm) on ultrasound imaging.
4. The patient should be candidate for neoadjuvant chemotherapy treatment used in the study as evaluated by the treating physician (assisted by gene expression signatures with a result indicating an intermediate or high risk of disease recurrence, or by tumor core biopsy with an Ki67 average labeling index ≥ 20%).
5. WHO performance status ≤ 1
6. Adequate hematological function with absolute neutrophil count (ANC) ≥1.0 x 109/L AND platelet count ≥100 x 109/L AND hemoglobin ≥9 g/dL (may be transfused to maintain or exceed this level)
7. Adequate liver function with total bilirubin <1.5 x upper limit of normal (ULN) AND Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) <2.5 x ULN× upper limit of normal (ULN). Patients with confirmed Gilberts syndrome may be included in the study despite elevated bilirubin.
8. Adequate renal function with serum creatinine ≤1.5 x ULN and Creatinine clearance (CrCL) >50 mL/min per the Cockcroft-Gault formula (using actual body weight).
AND
Urine dipstick for proteinuria <2+. Patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein in 24 hours
9. For patients to be eligible for post-chemotherapy endocrine treatment with or without capivasertib (all criteria apply):
• ER positive score in ≥50% of the tumor cells
• Viable tumor at thru-cut biopsy sampled after neoadjuvant chemotherapy
• Measurable disease on ultrasound with diameter 15 mm or more.
10. International normalized ratio (INR) ≤1.5 and APTT (cephotest) ≤1.5 x ULN within 7 days prior to enrolment
11. Women should not be pregnant or breast-feeding. Women with an intact uterus (unless amenorrhoeic for the last 24 months and postmenopausal levels of FSH, LH and oestradiol) must have a negative serum pregnancy test within 28 days prior to inclusion into the study.
12. Female patients of childbearing potential should be willing to use 2 forms of highly reliable methods of contraception from the time of screening until 4 weeks after discontinuing study treatment OR Patients must have evidence of an inability to bear children by fulfilling 1 of the following criteria at screening: - Post-menopausal – defined as aged >50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
13. Male patients should use barrier contraception (ie, condoms) from the time of screening until 16 weeks after discontinuation of study drug. It is not known whether the preclinical changes seen in the male animal reproductive organs, after treatment with capivasertib, will be fully reversible or will permanently affect the ability to produce healthy sperm following treatment. Therefore, if male patients may wish to father children in the future they should be advised to arrange for freezing of sperm samples prior to the start of study treatment.
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| E.4 | Principal exclusion criteria |
1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
2. Previous chemotherapy treatment for localized breast cancer less than 24 months before inclusion into study
3. Other earlier or concomitant carcinoma less than five years prior to the breast cancer diagnosis, except for BCC or in situ cervix cancer.
4. Any sign of metastatic disease on CT or bone scan.
5. Treatment with any other investigational agent, or participation in another clinical intervention trial within 21 days prior to enrolment.
6. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib
7. Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrolment or anticipation of the need for major surgery during study treatment, or minor surgery, including insertion of an indwelling catheter, within 24 hours prior to the first bevacizumab infusion.
8. Current or recent (within 10 days of first dose of bevacizumab):
• use of aspirin (>325 mg/day).
• use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes. Prophylactic use of anticoagulants is allowed.
9. Any of the following cardiac criteria at screening:
- Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram or multiple-gated acquisition [MUGA] scan.
- Mean resting corrected QT interval (QTc) >470 msec obtained from 2 consecutive ECGs
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia of Grade ≥1, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
- Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) grade ≥2
- Uncontrolled hypotension – SBP <90 mmHg and/or DBP <50 mmHg
10. Clinically significant abnormalities of glucose metabolism as defined by any of the following at screening:
- Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment
- HbA1c ≥8.0% (63.9 mmol/mol)
11. Previous allogeneic bone marrow transplant or solid organ transplant
12. Strong inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort), or drugs that are sensitive to inhibition of CYP3A4 within 1 week prior to the first dose of study treatment. For details, see Appendix (Appendix A)
13. History of hypersensitivity to active or inactive excipients of the study drug or drugs with a similar chemical structure or class to study drugs.
14. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg), active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
15. Evidence of any other disease, renal, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent
16. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Outcome Measure Part 1 (Chemotherapy):
The pathological complete response (pCR) defined as the complete disappearance of invasive cancer in the breast and locoregional lymph nodes, after 24 wks of chemotherapy in the signature positive patients with and without bevacizumab.
Primary Outcome Measure, Part 2 (Post chemotherapy):
The frequency of tumors with a downregulation of KI67 score to a level of complete cell cycle arrest (CCCA) defined as less than 2.7% positive cells at 2-3 weeks after the start of the therapy in patients treated with letrozole and capivasertib compared to patients treated with letrozole alone. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Outcome Measure Part 1 (Chemotherapy): After 24 wks of chemotherapy with or without bevacizumab.
Primary Outcome Measure, Part 2 (Post chemotherapy): At 2 to3 weeks after the start of letrozole and capivasertib or letrozole alone. |
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| E.5.2 | Secondary end point(s) |
Secondary Outcome Measure Part 1 (Chemotherapy):
The time from the inclusion into to the study until the appearance of any invasive breast cancer disease in nine-gene/protein (ViRP) signature positive patients randomized to treatment with chemotherapy in combination with bevacizumab or chemotherapy alone.
Secondary Outcome Measure Part 2 (post chemotherapy):
The time from the inclusion into to the study until the appearance of any invasive breast cancer disease in patients randomized to treatment with letrozole in combination with capivasertib, compared to treatment with letrozole alone.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Outcome Measure Part 1 (Chemotherapy): After a median of 5 yrs of follow-up
Secondary Outcome Measure Part 2 (post chemotherapy): After a median of 5 yrs of follow-up |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| 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 | 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 |
| Standard treatment according to guidelines |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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