Clinical trial NCT04305496: Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer
Official title: A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Breast Cancer Following Recurrence or Progression On or After Treatment With an Aromatase Inhibitor
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Locally Advanced (Inoperable) or Metastatic Breast Cancer
Keywords: Locally advanced (inoperable) or Metastatic Breast Cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-03-12
Enrollment: 818
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind Randomised Study
Primary purpose: TREATMENT

Brief summary: Phase III, double-blind, randomised study assessing the efficacy of capivasertib + fulvestrant vs placebo + fulvestrant for the treatment of patients with locally advanced (inoperable) or metastatic HR+/HER2- breast cancer following recurrence or progression on or after AI therapy.

Detailed description: Phase III, double-blind, randomised study assessing the efficacy of capivasertib + fulvestrant vs placebo + fulvestrant for the treatment of patients with locally advanced (inoperable) or metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) breast cancer following recurrence or progression on or after aromatase inhibitor (AI) therapy.

Eligibility criteria: Inclusion Criteria:

1. Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with an LHRH agonist. Patients are to have commenced concomitant treatment with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for the duration of the study
2. 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.
3. 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)
4. ECOG/WHO PS: 0-1
5. Patients are to have received treatment with an AI (aromatase inhibitor) containing regimen (single agent or in combination) and have:

   1. Radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of (neo)adjuvant treatment with an AI, OR
   2. Radiological evidence of progression while on prior AI administered as a treatment line for locally advanced or metastatic breast cancer (this does not need to be the most recent therapy)
6. Patients must have measurable disease according to RECIST 1.1 and/or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
7. FFPE tumour sample from primary/recurrent cancer for central testing

Exclusion Criteria:

1. Symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgement
2. More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic disease
3. 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 advanced breast cancer
4. Prior treatment with any of the following:

   1. AKT, PI3K and mTOR inhibitors
   2. Fulvestrant, and other SERDs
   3. Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks prior to study treatment initiation.
   4. 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.
5. Radiotherapy with a wide field of radiation up to 4 weeks before study treatment initiation (capivasertib/placebo) and/or radiotherapy with a limited field of radiation for palliation up to 2 weeks before study treatment initiation (capivasertib/placebo)
6. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment
7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids up to 4 weeks before study treatment initiation
8. Any of the following cardiac criteria:

   1. Mean resting QT interval corrected by Fridericia's formula (QTcF) \>470 msec obtained from 3 consecutive ECGs
   2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)
   3. Any factors that increase the risk of corrected QT interval (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
   4. 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
   5. Uncontrolled hypotension - systolic blood pressure \<90 mmHg and/or diastolic blood pressure \<50 mmHg
   6. 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:

   1. Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment
   2. HbA1c ≥8.0% (63.9 mmol/mol)
10. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if applicable)
11. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding

Primary outcomes:
measure: Progression-Free Survival (PFS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup
timeFrame: The time from date of randomisation to the date of progression or death due to any cause, whichever occurs earlier, up to approximately 51 months
Secondary outcomes:
measure: Overall Survival (OS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.
timeFrame: The time from date of randomisation to the date of death due to any cause up to 51 months
measure: Investigator assessment of PFS2 in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.
timeFrame: The time from the date of randomisation to the date of progression subsequent to the first subsequent therapy, or death due to any cause, whichever occurs earlier, up to approximately 51 months
measure: Response Rate (ORR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.
timeFrame: Up to Approximately 51 months
measure: Duration of Response (DoR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.
timeFrame: Up to Approximately 51 months
measure: Clinical Benefit Rate (CBR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.
timeFrame: Up to Approximately 51 months
measure: ocurrence/frequency of AEs and its relationship to study drugs (safety and tolerability) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup
timeFrame: Up to Approximately 51 months
measure: plasma concentration of capivasertib
timeFrame: Minimum plasma concentration (Cmin), plasma concentration 1 hour post-dose (C1h) and 4 hours post-dose (C4h) during cycles 1 and 2 (each cycle is 28 days)
measure: EORTC QLQ BR23(European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer specific module) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup where applicable
timeFrame: Up to Approximately 51 months
measure: The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup where applicable
timeFrame: Up to Approximately 51 months
measure: Time to definitive deterioration of the ECOG (Eastern Cooperative Oncology Group) performance status in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup where applicable
timeFrame: Up to approximately 51 months
Other outcomes:
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city: Seoul
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city: Seoul
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city: Seoul
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city: Suwon-si
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city: Suwon-si
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city: Arequipa
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city: Lima
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city: Bydgoszcz
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country: Russian Federation
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city: Madrid
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city: Madrid
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city: Tainan
country: Taiwan
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country: Taiwan
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country: Taiwan
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country: Taiwan
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country: Taiwan
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facility: Research Site
city: London
country: United Kingdom
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city: Manchester
country: United Kingdom
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city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
References: