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Capivasertib + Palbociclib + Fulvestrant for HR+/HER2- Advanced Breast Cancer (CAPItello-292). (CAPItello-292)

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ClinicalTrials.gov Identifier: NCT04862663
Recruitment Status : Recruiting
First Posted : April 28, 2021
Last Update Posted : May 17, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE March 17, 2021
First Posted Date  ICMJE April 28, 2021
Last Update Posted Date May 17, 2021
Actual Study Start Date  ICMJE May 10, 2021
Estimated Primary Completion Date October 21, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2021)
  • Phase Ib: 1. The number of participants with dose-limiting toxicity, as defined in the protocol. [ Time Frame: Within the first 28 day cycle. ]
    Dose-limiting toxicity as described in the protocol that is not related to disease progression, intercurrent illness or concomitant medications and that, despite optimal therapeutic intervention, meets protocol-defined criteria.
  • Phase Ib: 2. The number of participants with treatment-related adverse events. [ Time Frame: From baseline up to approximately 24 months. ]
    Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of participants with treatment-related adverse events.
  • Phase Ib: 3. The number of participants with treatment-related serious adverse events. [ Time Frame: From baseline up to approximately 24 months. ]
    Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of participants with treatment-related adverse events.
  • Phase III: 1. Progression Free Survival (PFS). [ Time Frame: Up to approximately 33 months. ]
    Progression Free Survival (PFS) is defined as time from randomization until progression per RECIST v1.1. as assessed by the investigator or death due to any cause.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2021)
  • Phase Ib: 1. PK parameters for palbociclib: Cmax. [ Time Frame: Cycle 0 (Cycle 0 is 3 days), Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 1 is 28 days). ]
    Maximum observed plasma (peak) drug concentration.
  • Phase Ib: 2. PK parameters for palbociclib: AUC0-72h. [ Time Frame: Cycle 0 (Cycle 0 is 3 days). ]
    Partial area under the plasma concentration-time curve from zero to 72 hours post-dose.
  • Phase Ib: 3. PK parameters for palbociclib: AUC0-24h. [ Time Frame: Cycle 0 (Cycle 0 is 3 days), Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 1 is 28 days). ]
    Partial area under the plasma concentration-time curve from zero to 24 hours post-dose.
  • Phase Ib: 4. PK parameters for palbociclib: Cmin. [ Time Frame: Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 0 is 3 days and Cycle 1 is 28 days). ]
    Minimum observed plasma drug concentration.
  • Phase Ib: 5. PK parameters for capivasertib: Cmax. [ Time Frame: Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days). ]
    Maximum observed plasma (peak) drug concentration.
  • Phase Ib: 6. PK parameters for capivasertib: AUC0-12h. [ Time Frame: Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days). ]
    Partial area under the plasma concentration-time curve from zero to 12 hours post-dose.
  • Phase Ib: 7. PK parameters for capivasertib: Cmin. [ Time Frame: Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days). ]
    Minimum observed plasma drug concentration.
  • Phase Ib: 8. Objective Response Rate (ORR). [ Time Frame: Up to approximately 24 months. ]
    Objective Response Rate (ORR) is defined as the proportion of patients with measurable disease at baseline who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by the investigator at local site per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
  • Phase Ib: 9. Clinical Benefit Rate (CBR) at 24 weeks. [ Time Frame: Up to approximately 24 months. ]
    Clinical Benefit Rate (CBR) 24 weeks is defined as the percentage of patients who have a CR or PR or who have SD per RECIST v1.1 as assessed by the investigator at local site for at least 23 weeks after date of first dose.
  • Phase Ib: 10. Duration of Response (DoR). [ Time Frame: Up to approximately 24 months. ]
    Duration of Response (DoR) will be defined as the time from the date of first documented confirmed response until date of documented progression per RECIST v1.1 as assessed by the investigator at local site or death due to any cause.
  • Phase Ib: 11. Progression Free Survival (PFS). [ Time Frame: Up to approximately 24 months. ]
    Progression Free Survival (PFS) is defined as time from date of first dose until progression per RECIST v1.1. as assessed by the investigator at local site or death due to any cause.
  • Phase III: 1. Overall Survival (OS). [ Time Frame: Up to approximately 60 months. ]
    Overall Survival (OS) - time from randomisation until the date of death due to any cause.
  • Phase III: 2. Progression Free Survival (PFS) in PIK3CA/ AKT1/ PTEN-altered population. [ Time Frame: Up to approximately 33 months. ]
    Progression Free Survival (PFS) - time from randomisation until progression per RECIST v 1.1 as assessed by the PI or death due to any cause.
  • Phase III: 3. Progression Free Survival 2 (PFS2). [ Time Frame: Up to approximately 60 months. ]
    Progression Free Survival (PFS2) - time from randomisation to the earliest of the progression event, subsequent to first therapy or death.
  • Phase III: 4. Objective Response Rate (ORR). [ Time Frame: Up to approximately 33 months. ]
    Objective Response Rate (ORR) - the proportion of patients who have a complete or partial response.
  • Phase III: 5. Duration of Response (DoR). [ Time Frame: Up to approximately 33 months. ]
    Duration of Response (DoR) - the time from the date of first documented response until the date of progression or death.
  • Phase III: 6. Clinical Benefit Rate (CBR) at 24 weeks. [ Time Frame: Up to approximately 33 months. ]
    Clinical Benefit Rate (CBR) at 24 weeks-the % of patients who have a CR or PR or who have SD for at least 23 weeks after randomization.
  • Phase III: 7. EORTC QLQ-30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items). [ Time Frame: Up to approximately 60 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.
  • Phase III: 8. 1.EORTC QLQ BR45 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer specific module). [ Time Frame: Up to approximately 60 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). Additional items yield two multi-item scales: a target symptom scale with three subscales (endocrine therapy, endocrine sexual and skin/mucosa) and a satisfaction scale. In addition, 3 single items are included that assess sexual enjoyment, future perspective and being upset by hair loss. 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 functioning, better HRQoL, or greater level of symptoms.
  • Phase III: 9. Time to definitive deterioration of the ECOG (Eastern Cooperative Oncology Group) performance status. [ Time Frame: Up to approximately 60 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.
  • Phase III: 10. Plasma concentration of capivasertib pre- and post-dose. [ Time Frame: Up to approximately 60 months. ]
    Plasma concentration of capivasertib pre-, and post-dose.
  • Phase III: 11. The number of participants with adverse events. [ Time Frame: Up to approximately 60 months. ]
    Data will include clinical observations, ECG parameters, clinical chemistry / haematology / glucose metabolism parameters and vital signs assessed as the number of participants with adverse events.
  • Phase III: 12. The number of participants with serious adverse events. [ Time Frame: Up to approximately 60 months. ]
    Data will include clinical observations, ECG parameters, clinical chemistry / haematology / glucose metabolism parameters and vital signs assessed as the number of participants with serious adverse events.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Capivasertib + Palbociclib + Fulvestrant for HR+/HER2- Advanced Breast Cancer (CAPItello-292).
Official Title  ICMJE A Phase Ib/III Randomised Study of Capivasertib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer
Brief Summary A Phase Ib/III Randomised Study of Capivasertib plus Palbociclib and Fulvestrant versus Placebo plus Palbociclib and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292).
Detailed Description This Phase Ib/III study (CAPItello-292) aims to evaluate the efficacy, safety and the degree of added benefit of capivasertib combined with palbociclib and fulvestrant in participants with endocrine-resistant locally advanced (inoperable) or metastatic HR+/HER2- breast cancer. Although the dosing regimens of capivasertib + fulvestrant and of palbociclib + fulvestrant are established, the dose and schedule for the triplet combination (capivasertib + palbociclib + fulvestrant) needs to be confirmed. Therefore, the initial dose finding Phase Ib part of the study will confirm the recommended Phase III doses (RP3D) and schedule of administration of capivasertib and palbociclib for the triplet combination including fulvestrant which will then be used in the Phase III part of this study.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase Ib: Open, Parallel groups allowed, recruiting approx. 72 participants. Phase III: Randomised, double blind, recruiting approx. 628 participants.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Locally Advanced (Inoperable) or Metastatic Breast Cancer
Intervention  ICMJE
  • Drug: Capivasertib
    Phase Ib: potential range 200 mg, 320 mg, 400 mg, all BD. Days 1 to 4 in each week of a 28-day treatment cycle Phase III: 400 mg (BD 4 days on 3 days off/week for 4 weeks), depending on tolerability observed in Phase Ib
  • Drug: Capivasertib Placebo
    Phase Ib: Not applicable Phase III: 400 mg (BD 4 days on 3 days off/week for 4 weeks), depending on tolerability observed in Phase Ib
  • Drug: Fulvestrant
    Phase Ib and Phase III: 500 mg (2 injections of 250 mg) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter
  • Drug: Palbociclib
    Phase Ib: potential range 75 mg, 100 mg, 125 mg. Once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete 28-day cycle Phase III: 125 mg (OD 21 days of 28- day cycle), depending on tolerability observed in Phase Ib
Study Arms  ICMJE
  • Experimental: Capivasertib Plus Palbociclib and Fulvestrant

    Drug: Capivasertib:

    Phase Ib: potential range 200 mg, 320 mg, 400 mg, all BD, 4days on/3 days off per week for 4 weeks (28 days cycle) Phase III: 400 mg BD, 4days on/3 days off per week for 4 weeks, depending on tolerability observed in Phase Ib.

    Drug: Palbociclib:

    Phase Ib: potential range 75, 100 or 125 mg (OD, dosed continually for 21 days out of 28 days).

    Phase III: 125 mg PO, OD, dosed continually for 21 days out of 28 days.

    Drug: Fulvestrant:

    Both phases: 500 mg IM, monthly (Day 1 of a 28-day cycle) with a loading dose of 500 mg 2 weeks after the first dose.

    Interventions:
    • Drug: Capivasertib
    • Drug: Fulvestrant
    • Drug: Palbociclib
  • Placebo Comparator: Placebo Plus Palbociclib and Fulvestrant
    Phase Ib: Not applicable. Phase III: 400 mg (BD 4 days on 3 days off/week for 4 weeks), depending on tolerability observed in Phase Ib
    Interventions:
    • Drug: Capivasertib Placebo
    • Drug: Fulvestrant
    • Drug: Palbociclib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 23, 2021)
700
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 15, 2027
Estimated Primary Completion Date October 21, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key inclusion criteria for both phases:

  1. Adult females (pre- and/or post-menopausal), and adult males.
  2. Histologically confirmed HR+/ HER2- breast cancer determined from the most recent tumour sample (primary or metastatic) per the American Society of Clinical Oncology and College of American Pathologists guideline. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor.
  3. Eligible for palbociclib and fulvestrant therapy as per investigator assessment.
  4. Adequate organ and bone marrow functions.
  5. Consent to provide a mandatory FFPE tumour sample.

Inclusion criteria only for phase III:

  1. Radiologic measurable relapse during neoadjuvant / adjuvant endocrine therapy or evidence of relapse within 12 months of completion of adjuvant therapy or disease progression during the initial 12 months of 1L endocrine therapy in locally advanced unresectable or metastatic breast cancer.
  2. Received up to a maximum of 1 lines of prior chemotherapy in the advanced setting.

Key exclusion criteria for both phases:

  1. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence.
  2. Radiotherapy with a wide field of radiation within 4 weeks prior to study treatment initiation and/or radiotherapy with a limited field of radiation for palliation within 2 weeks prior to study treatment initiation. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible independent of when it was received.
  3. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
  4. Persistent toxicities (CTCAE Grade >1) caused by previous anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca study physician.
  5. Spinal cord compression, brain metastases or leptomeningeal metastases unless asymptomatic, treated and stable and not requiring steroids within 4 weeks prior to study treatment initiation.
  6. Any of the following cardiac criteria at screening:

    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
    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
    6. . Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher)
  7. Any of these clinically significant abnormalities of glucose metabolism at screening:

    1. . diabetes mellitus type I or type II requiring insulin treatment
    2. . HbA1c ≥ 8.0% (63.9 mmol/mol)
  8. Previous allogeneic bone marrow transplant or solid organ transplant.

Key exclusion criteria for the phase III only:

1. Prior treatment with CDK4/6 inhibitors (any setting), a SERD (including unlicensed SERDs), allosteric mTOR inhibitors (e.g. everolimus), PI3K inhibitors (e.g. alpelisib) or AKT inhibitors.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Denmark,   Poland,   Sweden,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04862663
Other Study ID Numbers  ICMJE D361DC00001
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  ICMJE
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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

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 rerefer 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 deidentified 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
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP