Capivasertib plus Paclitaxel as First line Treatment for Locally Advanced (Inoperable) or Metastatic Triple Negative Breast Cancer (CAPItello290)
Scientific Title of Study
A Phase III Double blind Randomised Study Assessing the Efficacy and
Safety of Capivasertib plus Paclitaxel Versus Placebo plus Paclitaxel as First line Treatment for Patients with Histologically Confirmed, Locally Advanced
(Inoperable) or Metastatic Triple-Negative Breast Cancer (TNBC)
Capivasertib: Dose and frequency of dosing - will be given as an intermittent weekly dosing schedule. on weeks 1, 2, and 3 followed by 1 week off-treatment within each 28-day treatment cycle.
Route of administration - Oral
Duration of therapy - Study treatment will be continued until disease progression unless there is evidence of unacceptable toxicity, or if the patient requests to stop the study treatment.
Paclitaxel: Dose and frequency of dosing- Patients will receive 3 consecutive weekly infusions followed by 1 week off-treatment within each 28-day treatment cycle.
Route of administration - Intravenous infusion
Duration of therapy - Paclitaxel treatment will be continued for at least 6 cycles unless the patient experiences unacceptable toxicity that is attributed directly to treatment with paclitaxel.
Placebo plus Paclitaxel
Placebo: Dose and frequency of dosing - will be given on an intermittent weekly dosing schedule on weeks 1, 2, and 3 followed by 1 week off-treatment within each 28-day treatment cycle.
Route of administration - Oral Duration of therapy - Study treatment will be continued until disease progression unless there is evidence of unacceptable toxicity, or if the patient requests to stop the study treatment.
Paclitaxel: Dose and frequency of dosing- Patients will receive 3 consecutive weekly infusions followed by 1 week off-treatment within each 28-day treatment cycle
Route of administration - Intravenous infusion Duration of therapy - Paclitaxel treatment will be continued for at least 6 cycles unless the patient experiences unacceptable toxicity that is attributed directly to treatment with paclitaxel.
Patients are eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria apply:
1 Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical study protocol (CSP)
2 Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
3 For inclusion in the optional exploratory genetic and/or biomarker research, provision of signed and dated written genetic and/or biomarker informed consents, respectively, prior to collection of sample
If a patient declines to participate in the optional exploratory genetic research and/or the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.
4 Patients must be aged ≥18 years at the time of signing the ICF
Type of patient and disease characteristics:
5 Histologically confirmed breast cancer
6 Metastatic or locally advanced disease; 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)
7 Triple-negative disease, determined from the most recent tumour sample taken for diagnostic purposes (accompanied by an associated pathology report), defined as:
i) Negative for ER with <1% of tumour cells positive for ER on immunohistochemistry (IHC) or IHC score (Allred) of ≤2,
ii) Negative for PR with <1% of tumour cells positive for PR on IHC or IHC score (Allred) of ≤2 or PR unknown, and
iii) Negative for HER2 with 0, 1+ intensity on IHC or 2+ intensity on IHC and no evidence of amplification on in situ hybridisation as per the American Society of Clinical Oncology College of American Pathologists. HER2 guideline recommendations
8 Eligible for taxane monotherapy as per local investigator assessment
9 Patients must have:
i) At least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computer tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
ii) Lytic or mixed (lytic + sclerotic) bone lesions that can be assessed by CT or MRI in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
10 Consent to submit and provision of a mandatory FFPE sample for central testing. A FFPE tissue block from the most recently collected pre-randomisation tumour sample (primary or recurrent cancer) is preferred. If it is not possible to provide a tissue block, at least 20 freshly-cut unstained serial tumour slides are to be provided. Sample requirements are further described in the Pathology and Genomic Testing Manual.
11 Patients must be able to swallow and retain oral medication
12 ECOG/WHO performance status 0-1 with no deterioration over the previous 2 weeks and life expectancy of ≥12 weeks
13 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 capivasertib/placebo or until 6 months after discontinuing paclitaxel, whichever occurs later
Patients must have evidence of an inability to bear children by fulfilling 1 of the following criteria at screening:
i) Post-menopausal – defined as aged >50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
ii) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation
14 Female patients must not be breast-feeding and must have a negative pregnancy test prior to start of dosing
15 Male patients should use barrier contraception (ie, condoms) from the time of screening until 16 weeks after discontinuation of capivasertib/placebo or 6 months after discontinuing paclitaxel, whichever occurs later. 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
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1 Malignancies other than breast cancer within 5 years prior to treatment initiation (except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer)
2 Radiotherapy with a wide field of radiation within 4 weeks before the first dose of study treatment (capivasertib/placebo)
3 Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment
4 Pre-existing sensory or motor polyneuropathy ≥grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5)
5 With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment
6 Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment
7 Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
8 Any of the following cardiac criteria at screening:
i) Mean resting corrected QT interval (QTc) >470 msec obtained from 3 consecutive ECGs
ii) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)
iii) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, 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
iv) 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
v) Uncontrolled hypotension – SBP <90 mmHg and/or DBP <50 mmHg
vi) Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if an echocardiogram cannot be performed or is inconclusive).
9 Clinically significant abnormalities of glucose metabolism as defined by any of the following at screening:
i) Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment
ii) HbA1c ≥8.0% (63.9 mmol/mol)
10 Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values at screening:
i) Absolute neutrophil count <1.5 × 109/L
ii) Platelet count <100 × 109/L
iii) 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)]
iv) Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) >2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or >5 × ULN in the presence of liver metastases. Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate in the investigator’s judgement
v) Total bilirubin >1.5 × ULN (patients with confirmed Gilbert’s syndrome may be included in the study)
vi) 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
11 As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
12 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
13 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
14 Evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent
15 Previous allogeneic bone marrow transplant or solid organ transplant
16 Known immunodeficiency syndrome
17 Prior treatment with any of the following:
AKT, PI3K, and/or mTOR inhibitors
Any prior systemic therapy for inoperable locally advanced or metastatic disease
i) Capivasertib in the present study (ie, any dosing with capivasertib due to previous participation in this study)
ii) Chemotherapy in the (neo)adjuvant setting within 12 months from the end of chemotherapy to inclusion into this study
iii) Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
iv) Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment
v) Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long half-life (eg, biologics) as agreed by the sponsor
vi) 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 sensitive substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week prior to the first dose of study treatment. For details, see Appendix D
Prior/concurrent clinical study experience
18 Previous randomisation in this study
19 Participation in another clinical study with an investigational medicinal product (IMP) administered in the last 30 days or 5 half-lives, whichever is longer
20 History of hypersensitivity to active or inactive excipients of capivasertib or drugs with a similar chemical structure or class to capivasertib
21 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
22 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
23 History of hypersensitivity to paclitaxel or to any of the excipients
24 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Participant and Investigator Blinded
Progression-Free Survival (PFS): Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)
Overall Survival (OS): Overall Survival (OS)
The time from date of randomisation to the date of progression or death due to any cause, whichever occurs earlier, up to approximately 42 months
Investigator assessment of PFS2: PFS2 - time from randomisation to second progression or death due to any cause
Approximately up to 42 months
Response Rate (ORR): percentage of patients with at least one investigator-assessed visit response of complete or partial response (as assessed by the investigator, using RECIST 1.1
Approximately up to 42 months
Safety and tolerability of drugs by assessment of AEs/SAEs: Graded according to the National Cancer Institute (NCI CTCAE)
Approximately up to 42 months
Minimum plasma concentration(Cmin), plasma concentration1-2 hours post-dose (C1-2h) and 4 hours post-dose (C4h) during months 1 and 2: Plasma PK parameters derived from a population model as data permits
During months 1 and 2
EORTC QLQ BR23(European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer specific module): The self-administered instrument includes 23-items and yields 5 multi-item scores (body image, sexual functioning, arm symptoms, breast symptoms, and systemic therapy side effects).
Approximately up to 42 months
The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items): 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), and global health status/QoL scale, along with 5 individual item symptom scores (appetite loss, dyspnoea, insomnia, constipation, and diarrhoea
Approximately up to 42 months
Duration of Response (DoR): time from the date of first documented response until date of documented progression (as assessed by the investigator, using RECIST 1.1) or death in the absence of disease progression
Approximately up to 42 months
Clinical Benefit Rate (CBR): number of patients with complete or partial response or with stable disease maintained ≥24 weeks (as assessed by the investigator, using RECIST 1.1) divided by the number of patients in the analysis
Total Sample Size="800" Sample Size from India="50" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
This is a Phase III, double-blind, randomised study assessing the efficacy of capivasertib + paclitaxel vs placebo + paclitaxel as first-line treatment in patients with histologically confirmed, locally advanced (not amenable to resection with curative intent) or metastatic TNBC in the overall population and in the PIK3CA/AKT1/PTEN-altered sub-population (altered subgroup). ‘PIK3CA/AKT1/PTEN-altered’ refers to a prespecified subgroup of patients whose tumours harbour qualifying activating mutation in PIK3CA or AKT1 and/or qualifying inactivating alteration in PTEN
Initially, enrolment will be open to all eligible patients irrespective of the PIK3CA/AKT1/PTEN status of their tumour(s); however, the prevalence of the subgroup of patients qualifying for the altered subgroup will be monitored post-randomisation via central testing of formalin-fixed paraffin-embedded (FFPE) tumour samples collected before study entry. Based on emerging information during the course of the study, enrolment may be restricted to patients who qualify for the altered sub-population.
Approximately 800 patients will be randomised in a 1:1 ratio to treatment with either capivasertib + paclitaxel or placebo + paclitaxel.Randomisation will occur as soon as possible after commencement of screening and should be within 28 days of screening.
The randomisation scheme will be stratified on the following factors:
1 Visceral vs non-visceral disease
2 (Neo)adjuvant chemotherapy: yes vs no
3 Geographic region: China, Asia-Pacific (excluding China), United States, Rest of the World
( Visceral disease is defined as lung, liver (including biliary tract), brain, pleural and/or peritoneal involvement.)
Paclitaxel will be administered as a weekly single intravenous (IV) infusion. Patients will receive 3 consecutive weekly paclitaxel infusions followed by 1 week off-treatment within each 28-day treatment cycle.
Capivasertib/placebo will be continued until disease progression unless there is evidence of unacceptable toxicity, or if the patient requests to stop the study treatment.Paclitaxel treatment will be continued for at least 6 cycles unless the patient experiences unacceptable toxicity that is attributed directly to treatment with paclitaxel.If capivasertib/placebo is discontinued for reasons other than disease progression, the patient may continue on paclitaxel alone at the investigator’s discretion.Likewise, if paclitaxel is discontinued for reasons other than disease progression, the patient may continue on capivasertib/placebo alone at the investigator’s discretion.
An Independent Data Monitoring Committee (IDMC) will be established in order to assess the progress of the clinical study at regular intervals.This will include reviewing unblinded safety and tolerability data and the data from the interim futility analysis in the non-altered subgroup in order to recommend to AstraZeneca whether or not to limit recruitment to the altered subgroup only.