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A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Paclitaxel Versus Placebo + Paclitaxel as First-line Treatment for Patients with Histologically Confirmed, Locally Advanced (Inoperable) or Metastatic Triple-Negative Breast Cancer (TNBC)

PHRR190620-002157

D3614C00001

2019-CT0495

A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Paclitaxel Versus Placebo + Paclitaxel as First-line Treatment for Patients with Histologically Confirmed, Locally Advanced (Inoperable) or Metastatic Triple-Negative Breast Cancer (TNBC) (CAPItello)

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 ofpatients qualifying for the altered subgroup will be monitored post-randomisation via central
testing of 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. The list of eligible alterations is curated on the basis of the currently published literature for causal associations between pathogenicity and the alterations, using the AstraZeneca strategy for early-stage clinical studies as described by Carr et al 2016. The list of eligible variants will be defined and specified in the SAP prior to analysis.

Approximately 600-800 patients will be randomised, with half of the patients included in each arm. In Weeks 1, 2, and 3 of each 28-day cycle, patients will receive oral treatment with capivasertib 400 mg or placebo twice daily (4 days on and 3 days off, Days 2-5) and a single weekly IV infusion of paclitaxel 80 mg/m2 (Day 1). All patients will attend a screening visit within 28 days before starting study treatment.

 

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development
Start Date Duration in Months Target Completion Date Actual Completion Date
2019-07-01 36 2022-07-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR LTO-3000002234602
Institution Classification Region LTO #
None None None
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Scarlette De Luna scarlette.deluna@astrazeneca.com 16F Inoza Tower, 40th St. Bonifacio Global City, Taguig, Philippines 1634
Name E-Mail Institution and Institution Address
Scarlette De Luna scarlette.deluna@astrazeneca.com 16F Inoza Tower, 40th St. Bonifacio Global City, Taguig, Philippines 1634
Name Expertise Affiliation
Adonis Guancia, MD Oncology Riverside Medical Center
Annielyn Beryl Ong-Cornel, MD Onconolgy University of Perpetual Help DALTA Medical Center
Arthur Gregory Lui, MD Oncology Metro Davao Medical and Research Center
Cherry Pink Villa, MD Oncology St. Paul's Hospital of Iloilo, Inc.
Jerry Tan Chun Bing, MD Oncology Cebu Doctor's University College of Medicine
Ma. Luisa Abesamis-Tiambeng, MD Oncology Cardinal Santos Medical Center
Myra Flores ,MD Oncology Saint Louis University Hospital of the Sacred Heart
Project Location Institutional Ethics Review Board
Riverside Medical Center N/A
University of Perpetual Help DALTA Medical Center University of Perpetual Help DALTA Medical Center Ethics Review Committee
Metro Davao Medical and Research Center Metro Davao Medical and Research Center – Ethics Review Committee
St. Paul's Hospital of Iloilo, Inc. St. Paul’s Hospital Iloilo – Institutional Ethics Review Board
Cebu Doctor's University College of Medicine Cebu Doctors’ University Hospital Research Ethics Committee
Cardinal Santos Medical Center Cardinal Santos Medical Center Ethics Review Committee
Saint Louis University Hospital of the Sacred Heart N/A

Patients with Histologically Confirmed, Locally Advanced (Inoperable) or Metastatic Triple-Negative Breast Cancer

  • Investigator assessment (in accordance with RECIST 1.1) of PFS, defined as the time from date of randomisation to the date of progression or death due to any cause.
  • OS, defined as the time from date of randomisation to the date of death due to any cause

  • Investigator assessment (in accordance with RECIST 1.1) of PFS, defined as the time from date of randomisation to the date of progression or death due to any cause.
  • Investigator assessment of PFS2, defined as the time from randomisation until second disease progression or death due to any cause.
  • Investigator assessment (in accordance with RECIST 1.1) of ORR, DoR, and CBR.
  • AEs/SAEs; vital signs; collection of clinical chemistry, haematology, glucose metabolism parameters; ECGs parameters.
  • Plasma PK parameters derived from a population PK model of plasma concentrations and patient factors.
  • Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 scale/item scores including change from baseline and time to deterioration.

Recruiting

Clinical Trial

D3614C00001

20190312164438

2019-06-04

0000-00-00

30

Unspecified

Unspecified

01 Jul 2019

INCLUSION CRITERIA

Informed consent
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.

Age
4 Patients must be aged ≥18 years (aged ≥20 years in Japan) at the time of signing the ICF

Type of patient and disease characteristics
5 Histologically confirmed breast cancer
6 Metastatic or locally recurrent disease; locally recurrent 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:
 Negative for ER with <1% of tumour cells positive for ER on immunohistochemistry (IHC) or IHC score (Allred) of ≤2,
 Negative for PR with <1% of tumour cells positive for PR on IHC or IHC score (Allred) of ≤2 or PR unknown, and
 Negative for HER2 with 0, 1+ 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:
 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
 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

Reproduction
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 study treatment (see Section 5.3.3)
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
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 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

Medical conditions
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:
 Mean resting corrected QT interval (QTc) >470 msec obtained from 3 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, 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  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:
 Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment
 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:
 Absolute neutrophil count  Platelet count

 Haemoglobin 14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)]
 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
 Total bilirubin >1.5 × ULN (patients with confirmed Gilbert’s syndrome may be included in the study)
 Creatinine >1.5 × ULN concurrent with creatinine clearance 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

Prior therapy
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
 Capivasertib in the present study (ie, any dosing with capivasertib due to previous participation in this study)
 Chemotherapy in the (neo)adjuvant setting within 12 months from the end of chemotherapy to inclusion into this study

 Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
 Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment
 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
 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

Other exclusions
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 Previous randomisation in the present study
24 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding

 

 

Interventional

Capivasertib

Capivasertib, a novel pyrrolopyrimidine-derived compound, is a potent and selective oral inhibitor of all 3 isoforms of AKT (Davies et al 2012). To support the development of capivasertib in TNBC, a recent investigator-sponsored, randomised, double-blind, placebo-controlled, multicentre Phase II study (NCT02423603, PAKT) evaluated the combination of capivasertib + paclitaxel compared with placebo + paclitaxel in patients with TNBC (140 patients, randomised 1:1), who were chemotherapy-naive in the metastatic setting (Schmid et al 2018). The study demonstrated that the addition of capivasertib to first-line paclitaxel therapy resulted in significantly longer progression-free survival (PFS) (the primary endpoint) and overall survival (OS). There was a larger magnitude of benefit (PFS and OS) in a prespecified molecularly selected subgroup of patients whose tumours carry qualifying alterations in at least one of the PIK3CA, AKT1, and/or PTEN genes. The combination of capivasertib + paclitaxel was generally well tolerated, with a manageable safety profile, appropriate for this setting.

None

Randomized

Double Blind

Unspecified

Single

  • To determine the efficacy of capivasertib + paclitaxel vs placebo + paclitaxel by investigator assessment of PFS.
  • To determine the efficacy of capivasertib + paclitaxel vs placebo + paclitaxel by assessment of OS.

Phase III

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