NeoAdjuvant PErsonalized therapy in Estrogen Receptor positive breast cancer (NAPEER) - An open label phase II trial of endocrine treatment with or without capivasertib, followed by response assessment before neoadjuvant chemotherapy with bevacizumab (if ViRP signature positive)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

11 May 2022 → ongoing

Decision date (initial)

2024-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

External identifiers

EU CT number

2023-510093-13-00

EudraCT number

2021-005850-27

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Endocrine therapy: To assess the effect of neoadjuvant capivasertib in combination with letrozole or neoadjuvant letrozole alone in patients with hormone receptor positive HER2 negative breast cancer.
Chemotherapy : To assess the efficacy of neoadjuvant chemotherapy with or without bevacizumab in a pre-treatment selected subgroup, using a molecular signature, in patients with large (cT2 – cT4) hormone receptor positive, HER2 negative breast cancer.

Secondary objectives 2

1. Endocrine Therapy: The invasive disease-free survival in the treatment arms.
2. Chemotherapy: The invasive disease-free survival in the treatment arms.

Conditions and MedDRA coding

Patients with hormone receptor positive HER2 negative breast cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Capable of giving signed informed consent, which includes commitment to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this clinical study protocol (CSP)
2. 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.
3. 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).
4. 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.
5. 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. 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.
6. For patients to be eligible for endocrine treatment with or without capivasertib: ER positive score in ≥50% of the tumor cells
7. International normalized ratio (INR) ≤1.5 and APTT (cephotest) ≤1.5 x ULN within 7 days prior to enrolment.
8. Pregnant or breast-feeding women are not eligible for the study.
9. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
10. 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.
11. The patient should be eligible 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 labelling index ≥ 20%).
12. WHO performance status ≤ 1
13. 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).
14. 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.

Exclusion criteria 15

1. Involvement in the planning and/or conduct of the study (applies to both Investigator 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 basal cell carcinomas 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): 1. use of aspirin (>325 mg/day). 2. use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
9. Clinically significant abnormalities of glucose metabolism as defined by any of the following at screening: 1. Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment or 2. HbA1c ≥8.0% (63.9 mmol/mol)
10. Previous allogeneic bone marrow transplant or solid organ transplant.
11. 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).
12. History of hypersensitivity to active or inactive excipients of the study drug or drugs with a similar chemical structure or class to study drugs.
13. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
14. 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
15. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Treatment efficacy will for the primary end-point in chemotherapy part of the study be evaluated after the end of chemotherapy treatment.

Secondary endpoints 1

1. Treatment efficacy for the primary endpoint in endocrine therapy part of the study will be evaluated by the use of Ki67 staining and quantification in the thru-cut biopsy specimen obtained at the time of the response evaluation after 15 days of therapy (+/- 3 days).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital HF

Sponsor organisation

Oslo University Hospital HF

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital HF

Contact name

Olav Engebråten

Public contact point

Organisation

Oslo University Hospital HF

Contact name

Olav Engebråten

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications