Research study on the use of capivasertib together with fulvestrant in patients with advanced breast cancer who have relapsed/progressed to standard treatment reflecting actual clinical practice in Spain

Prior treatment

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.
• 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.
• Previous allogenic bone marrow or solid organ transplant
• History of hypersensitivity to active or inactive excipients of capivasertib, fulvestrant and LHRH agonists (if applicable, ie, concomitant LHRH agonist required in this study) or drugs with a similar chemical structure or class to capivasertib, fulvestrant or LHRH agonists (if applicable, ie, concomitant LHRH agonist required in this study).

Other illness

• Known immunodeficiency syndrome
• Evidence of dementia altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent.

Lab values

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
• One or more of the following: a. Mean resting corrected QT interval >470 ms, obtained from ECG performed at screening. b. History of QT prolongation associated with other medications that required discontinuation of that medication. c. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. d. Medical history significant for arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigator judgement with cardiologist consultation recommended. e. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, hypokalaemia of Grade >1, potential for Torsades de Pointes, congenital long QT syndrome. f. Experience of any of the following procedures or conditions in the preceding 3 months: coronary artery bypass graft, angioplasty, myocardial infarction, unstable angina pectoris. g. Congestive heart failure New York Heart Association (NYHA) ≥grade 2.
  • A disease burden that makes the patient ineligible for endocrine therapy per the investigator’s best judgement (eg, symptomatic visceral disease that is potentially lifethreatening in the short-term).
  • Prior/concomitant therapy. More than 2 lines of endocrine therapy or in combination with CDK4/6i for inoperable locally advanced or metastatic disease
  • More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for ABC.
• Prior/concomitant treatment with any of the following:  Prior treatment with AKT1, PIK3CA and mTOR inhibitors  Prior treatment with nitrosourea or mitomycin C within 6 weeks prior to study treatment initiation.  Prior treatment with any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents other than those specified in this protocol (e.g. hormonal therapy such us LHRH agonists) within 3 weeks prior to study treatment initiation. A longer washout period may be required for drugs with a long half-life (eg, biologics) as agreed by the sponsor.  Prior treatment with any small molecule within 3 half lives prior to study treatment initiation.  Prior treatment with potent 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 CYP3A4 inhibition within 1 week prior to study treatment initiation. NOTE: that adequate washout or dose reduction may be required for some CYP3A substrates with a narrow therapeutic window prior to initiating capivasertib dosing. For details, see Drug Interactions with capivasertib that affect capivasertib.  Any concomitant medication that may interfere with fulvestrant safety and effectiveness based on the prescribing information of fulvestrant and local clinical guidelines.  Any concomitant medication known to be associated with TdP. Information regarding drugs known to prolong the QT Interval and/or TdP can be found on the CredibleMeds website (http://crediblemeds.org).  Prior exposure to any antibody-based anticancer therapy within 4 weeks prior to study treatment initiation.  Concurrent use of herbal or natural products intended as treatment or prophylaxis for any type of cancer.  Prior treatment with radiotherapy within 2 weeks prior to the first dose of study intervention.  Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
  • Prior/Concurrent Clinical Study Experience - Previous capivasertib + fulvestrant treatment in the present study.
  • Participation in another clinical study with a study intervention or investigational medicinal device administered in the 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
  • Align with exclusion criteria discussing last dose of anticancer therapy if appropriate
• Except for alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment.
  • Leptomeningeal metastases.
  • Spinal cord compression, or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
  • Clinically significant abnormalities of glucose metabolism as defined by any of the following: a. HbA1c ≥8.0% (63.9 mmol/mol).
  • Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a. Absolute neutrophil count <1.5 × 109/L. b. Platelet count <100 × 109/L. c. Haemoglobin <9 g/dL (<5.59 mmol/L). [NOTE: any blood transfusion must be >14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)]. d. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) >2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or >5 × ULN in the presence of liver metastases. e. Total bilirubin >1.5 × ULN (Patients with confirmed Gilbert’s syndrome may be included in the study). f. Creatinine >1.5 × ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 × ULN.
  • As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV), including those who have confirmed COVID19. Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). Screening for chronic conditions is not required.
  • Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if applicable).

Other

• Unknown or non-altered PIK3CA/AKT1/PTEN-status
• Pregnant women (confirmed with positive pregnancy test) or breastfeeding women
• Patients who at time of data collection for this study are participating in or have participated in an interventional study that remains blinded.

• Adult (≥18 years) females, pre- and/or post-menopausal, and adult (≥18 years) males.
• Histologically confirmed HR+/HER2− breast cancer determined from the most recent tumour sample (primary or metastatic), as per the American Society of Clinical Oncology and College of American Pathologists guideline recommendations. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor. Therefore, tumours must be: - ER+ defined as ≥1% of tumour cells stain positive for ER on immunohistochemistry (IHC) or, if no percentage is available, then an Allred IHC score of ≥3/8, - Progesterone receptor positive defined as ≥1% of tumour cells stain positive for progesterone receptor on IHC or, if no percentage is available, then an Allred IHC score of ≥3/8; or progesterone receptor negative defined as <1% of tumour cells stain positive for progesterone receptor on IHC or, if no percentage is available, then an Allred IHC score of ≤2/8; or progesterone receptor unknown, and - HER2− defined as 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on in situ hybridisation (ISH), or if IHC not done, no evidence of amplification on ISH.
• Patient with tumours harbouring at least one PIK3CA/AKT1/PTEN‑qualifying alteration identified by NGS on tissue (or cell block if tissue is not available) OR another validated test. If the alteration is identified using a test other than a NGS panel evaluating the three genes (PIK3CA, AKT1, and PTEN) on tissue, the investigator must commit to perform the NGS test on tissue (or on cell block if tissue is not available) within 45 days. The NGS result is not required for treatment initiation. Note: Exceptionally, if the PIK3CA/AKT1/PTEN alteration is identified by NGS in ctDNA and neither tissue nor a cell block is available, the patient may still be included in the study. In these situations, the investigator must document the reason for the unavailability of tissue samples.
  • Metastatic or locally advanced disease with radiological or objective evidence of recurrence or progression (the cancer should have shown progression during or after most recent therapy); locally advanced disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible).
  • Patients are to have received treatment with an ET in combination with CDK4/6i and have: a. Radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of (neo)adjuvant treatment with an ET with CDK4/6i, OR b. Radiological evidence of progression while on prior ET with CDK4/6i administered as a treatment line for locally advanced or metastatic breast cancer. NOTE: ET + CDK4/6i does not need to be the most recent therapy for locally advanced or metastatic disease but prior exposure is required.
• Informed consent provided by patient (or a legally acceptable representative) a. Including a pre-screening consent to screen in a FFPE tumour sample or cell-block at baseline for PI3K/AKT pathway altered (PIK3CA/AKT1/PTEN) local testing if this has not been previously performed by a NGS panel evaluating the three genes (PIK3CA, AKT1, PTEN) on tissue. Exceptions apply if these alterations have been identified through NGS in ctDNA and there is no tissue or cell block available. b. Additionally, for inclusion in the exploratory genetic and/or biomarker research, provision of signed and dated written genetic and/or biomarker informed consents, respectively, to collect blood samples for central testing for PI3K/AKT pathway altered (PIK3CA/AKT1/PTEN) and additional translational biomarker assessments at baseline, cycle 2 day 1 and at end of treatment, and to collect baseline tissue or cell block for biomarker research. Only those patients for whom a PIK3CA/AKT1/PTEN alteration has been confirmed in ctDNA and no tissue or cell block is available will not be required to provide a tumour sample.
  • Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) performance status ≤ 2 at enrollment. NOTE: not more than 20% of patients with ECOG PS2 will be allowed; once this limit is met, additional enrolled patients must have ECOG PS <2.
  • Pre-menopausal patients with ovarian suppression induced by LHRH agonist should agree to use 2 forms of highly effective methods of accepted contraception to prevent pregnancy during the study and for 2 years after the last dose of fulvestrant, or until 16 weeks after discontinuing capivasertib whichever occurs later.
  • Male patients should use barrier contraception (ie, condoms) from the time of screening until 2 years after the last dose of fulvestrant or until 16 weeks after discontinuation of capivasertib, whichever occurs later. Male patients wishing to father children in the future should be advised to arrange for the freezing of sperm prior to the start of study treatment. NOTE: Female partners should be advised to use accepted contraception during their partner’s participation in the study and for 2 years after the last dose of fulvestrant or until 16 weeks after discontinuing capivasertib, whichever occurs later.