Clinical Trials /

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

NCT04305496

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 HR+/HER2− breast cancer following recurrence or progression on or after AI therapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2Breast 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

Clinical Trial IDs

  • ORG STUDY ID: D3615C00001
  • NCT ID: NCT04305496

Conditions

  • Locally Advanced (Inoperable) or Metastatic Breast Cancer

Interventions

DrugSynonymsArms
FulvestrantCapivasertib + fulvestrant
CapivasertibCapivasertib + fulvestrant
PlaceboPlacebo + fulvestrant

Purpose

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+/HER2breast 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.
    

Trial Arms

NameTypeDescriptionInterventions
Capivasertib + fulvestrantExperimentalFulvestrant: 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.
  • Fulvestrant
  • Capivasertib
Placebo + fulvestrantPlacebo ComparatorFulvestrant: 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.
  • Fulvestrant
  • Placebo

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 at least 4
             weeks prior to Cycle 1, Day 1 and must be willing to continue on it for the duration
             of the study

          2. Histologically confirmed HR+/HER2breast 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; 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 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 sensitive substrates of CYP3A4,
                  CYP2C9 and/or CYP2D6 with a narrow therapeutic window 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 corrected QT interval (QTc) >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 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 (if
             applicable)

         11. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)
Measure:Overall Survival (OS)
Time Frame:The time from date of randomisation to the date of death due to any cause up to 51 months
Safety Issue:
Description:Overall Survival (OS)
Measure: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
Safety Issue:
Description:PFS2 - time from randomisation to second progression by investigator assessment
Measure:Response Rate (ORR)
Time Frame:Up to Approximately 51 months
Safety Issue:
Description: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)
Measure:Duration of Response (DoR)
Time Frame:Up to Approximately 51 months
Safety Issue:
Description: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
Measure:Clinical Benefit Rate (CBR)
Time Frame:Up to Approximately 51 months
Safety Issue:
Description: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)
Measure:ocurrence/frequency of AEs and its relationship to study drugs (safety and tolerability)
Time Frame:Up to Approximately 51 months
Safety Issue:
Description:AEs graded according to the National Cancer Institute (NCI CTCAE)
Measure: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)
Safety Issue:
Description:plasma concentration of capivasertib pre-dose and post-dose (C1h and C4h) in the overall population
Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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
Measure:Time to definitive deterioration of the ECOG (Eastern Cooperative Oncology Group) performance status
Time Frame:Up to approximately 51 months
Safety Issue:
Description: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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Locally advanced (inoperable) or Metastatic Breast Cancer

Last Updated

March 11, 2020