Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC

Study Overview
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Brief Summary
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Phase III Study of Capivasertib + Paclitaxel versus Placebo + Paclitaxel as First line Treatment for Patients with Locally Advanced or Metastatic Triple-negative Breast Cancer (TNBC)

Detailed Description
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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)

Official Title
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A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib/+Paclitaxel vs Placebo+Paclitaxel as First-line Treatment for Patients With Locally Advanced (Inoperable) or Metastatic TNBC.

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: Capivasertib
* Drug: Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed TNBC from most recently collected tumour tissue sample Metastatic or locally recurrent disease; locally recurrent disease most not be amenable to resection with curative intent (patient who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible) ECOG/WHO PS: 0-1 Measurable disease according to RECIST 1.1 and/or lytics or mixedbone lesions that can be assessed by CT or MRI in the absence of measurable disease FFPE tumour sample from primary/recurrent cancer Exclusion Criteria: Prior Chemotherapy in the neoadjuvant or adjuvant setting within 6 months from the end of chemotherapy to the date of randomization; taxane chemotherapy in the neoadjuvant or adjuvant setting within 12 months from the end of chemotherapy to the start of randomization Prior systematic therapy for inoperable locally advanced or metastatic disease Prior treatment with any of the treatments listed below. Patients are not eligible to enter the study if they have received any of the medications specified below or are unable to meet the cautions and restrictions: AKT, PI3K, and/or mTOR inhibitors Capivasertib in the present study (ie, any dosing with capivasertib due to previous participation in this study) 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 halflife (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 drugs that are sensitive to CYP3A4 inhibition within 1 week prior to the first dose of study treatment. Radiotherapy with a wide field of radiation within 4 weeks before the first dose of study treatment (capivasertib/placebo) Pre-existing sensory or motor polyneuropathy ≥grade 2 according to NCI CTCAE v5 With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment 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 <90 mmHg and/or DBP <50 mmHg Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiplegated acquisition [MUGA] scan if an echocardiogram cannot be performed or is inconclusive). 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) Inadequate bone marrow reserve or organ function at screening Currently pregnant (confirmed with positive pregnancy test) or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind Randomised Study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capivasertib + Paclitaxel<br>Paclitaxel: Intravenous infusion. 3 consecutive weekly infusions of 80 mg/m2 (given on Day 1 of Weeks 1, 2, and 3), followed by 1 week off-treatment within each 28-day treatment cycle. Capivasertib: Oral tablets. 400 mg of Capivasertib (2 tablets) BD given on an intermittent weekly dosing schedule. Dosed on Days 2 to 5 of Weeks 1, 2, and 3 followed by 1 week off-treatment within each 28-day treatment cycle. | Drug: Capivasertib<br>* 400 mg (2 oral tablets) given on an intermittent weekly dosing schedule. Dosed on Days 2 to 5 of Weeks 1, 2, and 3 followed by 1 week off-treatment within each 28-day treatment cycle. 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.<br>* Other names: AZD5363;Drug: Paclitaxel<br>* 80 mg/m2 concentrate for solution for infusion, 3 consecutive weekly infusions of 80 mg/m2 (given on Day 1 of Weeks 1, 2, and 3), followed by 1 week off-treatment within each 28-day treatment cycle. Paclitaxel treatment will be continued for at least 6 cycles unless the patient experiences unacceptable toxicity that is attributed directly to treatment with paclitaxel.<br>|
| Placebo Comparator: Placebo + Paclitaxel<br>Paclitaxel: Intravenous infusion. 3 consecutive weekly infusions of 80 mg/m2 (given on Day 1 of Weeks 1, 2, and 3), followed by 1 week off-treatment within each 28-day treatment cycle. Placebo: Oral tablets. 400 mg of Placebo (2 tablets) BD given on an intermittent weekly dosing schedule. Dosed on Days 2 to 5 of Weeks 1, 2, and 3 followed by 1 week off-treatment within each 28-day treatment cycle. | Drug: Paclitaxel<br>* 80 mg/m2 concentrate for solution for infusion, 3 consecutive weekly infusions of 80 mg/m2 (given on Day 1 of Weeks 1, 2, and 3), followed by 1 week off-treatment within each 28-day treatment cycle. Paclitaxel treatment will be continued for at least 6 cycles unless the patient experiences unacceptable toxicity that is attributed directly to treatment with paclitaxel.<br>Drug: Placebo<br>* Placebo: Oral tablets. 400 mg of Placebo (2 tablets) BD given on an intermittent weekly dosing schedule. Dosed on Days 2 to 5 of Weeks 1, 2, and 3 followed by 1 week offtreatment within each 28-day treatment cycle<br>* Other names: Placebo tablets to match capivasertib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) | The time from date of randomisation to the date of death due to any cause up to approximately 42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1) | The time from date of randomization 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 | Time from randomization to second progression or death due to any cause up to approximately 42 months | 
| Response Rate (ORR) | 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) | Up to approximately 42 months | 
| Safety and tolerability of drugs by assessment of AEs/SAEs | Graded according to the National Cancer Institute (NCI CTCAE) | Up to approximately 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). Items are scored on a 4-point verbal rating scale: Not at All, A Little, Quite a Bit, and Very Much. Scores are transformed to a 0 to 100 scale, where higher scores indicate better unctioning, better HRQoL, or greater level of symptom. | 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. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 Scoring Manual (Fayers et al. 2001). Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales/scores represent greater symptom severity. | approximately up to 42 months | 
| Duration of Response (DoR) | 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. | Up to approximately 42 months | 
| Clinical Benefit Rate (CBR) | 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 | Up to approximately 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer;, Triple-negative Breast Cancer