Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer (CAPItello-291)

• ClinicalTrials.gov Identifier: NCT04305496
• Recruitment Status: Active, not recruiting
• First Posted: March 12, 2020
• Last Update Posted: May 30, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: February 20, 2020
• First Posted Date: March 12, 2020
• Last Update Posted Date: May 30, 2023
• Actual Study Start Date: April 16, 2020
• Actual Primary Completion Date: August 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2022)

Progression-Free Survival (PFS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup [ Time Frame: 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 ]

Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)

Original Primary Outcome Measures (submitted: March 11, 2020)

Progression-Free Survival (PFS) in the overall population [ Time Frame: 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 ]

Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)

Current Secondary Outcome Measures (submitted: April 14, 2022)

• Overall Survival (OS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup. [ Time Frame: The time from date of randomisation to the date of death due to any cause up to 51 months ]
  Overall Survival (OS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup
• Investigator assessment of PFS2 in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup. [ Time Frame: 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 ]
  PFS2 - time from randomisation to second progression by investigator assessment
• Response Rate (ORR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup. [ Time Frame: Up to Approximately 51 months ]
  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)
• Duration of Response (DoR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup. [ Time Frame: Up to Approximately 51 months ]
  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
• Clinical Benefit Rate (CBR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup. [ Time Frame: Up to Approximately 51 months ]
  number of patients with complete or partial response or with stable disease maintained ≥24 weeks after randomisation (as assessed by the investigator, using RECIST 1.1)
• 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 [ Time Frame: Up to Approximately 51 months ]
  AEs graded according to the National Cancer Institute (NCI CTCAE)
• plasma concentration of capivasertib [ Time Frame: 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) ]
  plasma concentration of capivasertib pre-dose and post-dose (C1h and C4h) in the overall population
• 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 [ Time Frame: Up to Approximately 51 months ]
  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
• 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 [ Time Frame: Up to Approximately 51 months ]
  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
• 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 [ Time Frame: Up to approximately 51 months ]
  Time from randomisation to the earlier of the date of the first definitive deterioration or death due to any cause. Deterioration is defined as a 1-point decrease in ECOG score from baseline, and the deterioration is considered definitive if no improvements in the ECOG performance status are observed at a subsequent time of measurement during the treatment period, or at no further assessments following the time point where the deterioration is observed

Original Secondary Outcome Measures (submitted: March 11, 2020)

• PFS in PIK3CA/AKT1/PTEN-altered subgroup [ Time Frame: 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 ]
  Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)
• Overall Survival (OS) [ Time Frame: The time from date of randomisation to the date of death due to any cause up to 51 months ]
  Overall Survival (OS)
• Investigator assessment of PFS2 [ Time Frame: 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 ]
  PFS2 - time from randomisation to second progression by investigator assessment
• Response Rate (ORR) [ Time Frame: Up to Approximately 51 months ]
  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)
• Duration of Response (DoR) [ Time Frame: Up to Approximately 51 months ]
  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
• Clinical Benefit Rate (CBR) [ Time Frame: Up to Approximately 51 months ]
  number of patients with complete or partial response or with stable disease maintained ≥24 weeks after randomisation (as assessed by the investigator, using RECIST 1.1)
• ocurrence/frequency of AEs and its relationship to study drugs (safety and tolerability) [ Time Frame: Up to Approximately 51 months ]
  AEs graded according to the National Cancer Institute (NCI CTCAE)
• plasma concentration of capivasertib [ Time Frame: 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) ]
  plasma concentration of capivasertib pre-dose and post-dose (C1h and C4h) in the overall population
• EORTC QLQ BR23(European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer specific module) [ Time Frame: Up to Approximately 51 months ]
  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
• The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items) [ Time Frame: Up to Approximately 51 months ]
  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
• Time to definitive deterioration of the ECOG (Eastern Cooperative Oncology Group) performance status [ Time Frame: Up to approximately 51 months ]
  Time from randomisation to the earlier of the date of the first definitive deterioration or death due to any cause. Deterioration is defined as a 1-point decrease in ECOG score from baseline, and the deterioration is considered definitive if no improvements in the ECOG performance status are observed at a subsequent time of measurement during the treatment period, or at no further assessments following the time point where the deterioration is observed

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Double-blind Randomised Study

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Locally Advanced (Inoperable) or Metastatic Breast Cancer

Intervention

• Drug: Fulvestrant
  Patients will be administered 500 mg (2 injections) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter
• Drug: Capivasertib
  400 mg BD (2 tablets of 200 mg taken twice a day = total daily dose 800 mg) given on an intermittent weekly dosing schedule. Patients will be dosed on Days 1 to 4 in each week of a 28-day treatment cycle
• Drug: Placebo
  Placebo to match 400 mg BD (2 tablets of placebo to match 200 mg taken twice daily = placebo to match total daily dose of 800 mg) given on an intermittent weekly dosing schedule. Patients will be dosed on Days 1 to 4 in each week of a 28-day treatment cycle

Study Arms

• Experimental: Capivasertib + fulvestrant

  Fulvestrant: 2 intramuscular injections of 500 mg given on Day 1 of Weeks 1 and 3 of cycle 1, and then on Day 1, Week 1 of each cycle thereafter.

  Capivasertib: 400 mg (2 oral tablets) BD given on an intermittent weekly dosing schedule. Dosed on Days 1 to 4 in each week of a 28-day treatment cycle.

  Interventions:

  • Drug: Fulvestrant
  • Drug: Capivasertib
• Placebo Comparator: Placebo + fulvestrant

  Fulvestrant: 2 intramuscular injections of 500 mg given on Day 1 of Weeks 1 and 3 of cycle 1, and then on Day 1, Week 1 of each cycle thereafter.

  Placebo: 400 mg (2 oral tablets) BD given on an intermittent weekly dosing schedule. Dosed on Days 1 to 4 in each week of a 28-day treatment cycle.

  Interventions:

  • Drug: Fulvestrant
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 1, 2023): 818
• Original Estimated Enrollment (submitted: March 11, 2020): 834
• Estimated Study Completion Date: June 7, 2024
• Actual Primary Completion Date: August 15, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Canada, China, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Peru, Poland, Russian Federation, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04305496
• Other Study ID Numbers: D3615C00001; 2019-003629-78 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: May 2023