Recruiting NCT04862663

Capivasertib + CDK4/6i + Fulvestrant for Advanced/Metastatic HR+/HER2- Breast Cancer (CAPItello-292)

Phase III Interventional Locally Advanced (Inoperable) or Metastatic Breast Cancer

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied: The protocol lists: Capivasertib, Fulvestrant, Palbociclib, Ribociclib.
Who it may be relevant to: Registry conditions: Locally Advanced (Inoperable) or Metastatic Breast Cancer. Basic parameters: 18 years — 99 years · All.
What needs checking: Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place: United States, Argentina, Australia, Belgium, Brazil +18
Next step: Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

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Official title

A Phase Ib/III, Open-label, Randomised Study of Capivasertib Plus CDK4/6 Inhibitors and Fulvestrant Versus CDK4/6 Inhibitors and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292)

Overview

A Phase Ib/III Open-label, Randomised Study of Capivasertib plus CDK4/6 Inhibitors and Fulvestrant versus CDK4/6 Inhibitors 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 CDK4/6i and fulvestrant in participants with locally advanced (inoperable) or metastatic HR+/HER2- breast cancer. Although the dosing regimens of capivasertib + fulvestrant and of CDK4/6i + fulvestrant are established separately, the dose and schedule for the triplet combinations (capivasertib + CDK4/6i + fulvestrant) need to be confirmed. Therefore, the initial dose finding Phase Ib part of the study will determine the recommended Phase III doses (RP3D) of the triplet combinations. The Phase III part of the study will evaluate the efficacy, safety and the degree of added benefit of the triplet combinations of capivasertib and fulvestrant with investigator's choice of CDK4/6i (either palbociclib or ribociclib at safe and tolerable doses, once identified) in comparison with a control arm (fulvestrant + investigator's choice of CDK4/6i \[palbociclib or ribociclib\]) in a ER+ HER2- maC high risk population that did not receive prior endocrine therapy in the advanced setting.

Interventions

Drug Capivasertib
Phase Ib: Capivasertib 320 mg/ 400 mg administered PO BD 4 days on /3 days off per week for 4 weeks (28 days cycle) Phase III: : Capivasertib, administered PO BD 4 days on / 3 days off per week for 4 weeks (28 days cycle) at the dose confirmed in the phase Ib portion
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: 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: Administered once daily for 21 days of 28-day cycle, at the dose of 125 mg.
Drug Ribociclib
Phase Ib: 200 mg/ 400 mg/ 600 mg. Once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete 28-day cycle Phase III: Administered once daily for 21 days of 28-day cycle, at the dose confirmed in the phase 1b portion.
Drug Abemaciclib
Phase Ib: 50 mg/ 100 mg/ 150 mg. Twice daily for 28 consecutive days to comprise a complete 28-day cycle

Primary outcome measures

Phase Ib: 1. The number of participants with dose-limiting toxicity, as defined in the protocol. [Time frame: Within the first 28 day cycle.]
Phase Ib: 2. The number of participants with treatment-related adverse events. [Time frame: From baseline up to approximately 36 months.]
Phase Ib: 3. The number of participants with treatment-related serious adverse events. [Time frame: From baseline up to approximately 36 months.]
Phase III: 1. Progression Free Survival (PFS). [Time frame: Up to approximately 47 months.]

Secondary outcome measures (12)

Phase Ib: 1. PK parameters for Palbociclib, Ribociclib, Abemaciclib: Cmax. [Time frame: Cycle 0 (Cycle 0 is 3 days), Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 1 is 28 days).]
Phase Ib: 2. PK parameters for Palbociclib, Ribociclib, Abemaciclib: AUC0-72h. [Time frame: Cycle 0 (Cycle 0 is 3 days).]
Phase Ib: 3. PK parameters for Palbociclib, Ribociclib, Abemaciclib: 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).]
Phase Ib: 4. PK parameters for Palbociclib, Ribociclib, Abemaciclib: Cmin. [Time frame: Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 0 is 3 days and Cycle 1 is 28 days).]
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).]
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).]
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).]
Phase Ib: 8. Objective Response Rate (ORR). [Time frame: Up to approximately 36 months.]
Phase Ib: 9. Clinical Benefit Rate (CBR) at 24 weeks. [Time frame: Up to approximately 36 months.]
Phase Ib: 10. Duration of Response (DoR). [Time frame: Up to approximately 36 months.]
Phase Ib: 11. Progression Free Survival (PFS). [Time frame: Up to approximately 36 months.]
Phase III: 1. Overall Survival (OS). [Time frame: Up to approximately 69 months.]

Eligibility criteria

Key inclusion criteria for both phases:

Adult females (pre-/peri-/ and post-menopausal), and adult males.
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.
Eligible for fulvestrant therapy and at least one of the following: palbociclib, ribociclib, or abemaciclib, as per local investigator assessment. Previous tolerance to specific CDK4/6 inhibitors and dose levels required.
Adequate organ and bone marrow functions.
Consent to provide a mandatory FFPE tumour sample.

Key inclusion criteria only for phase III:

Previous treatment with an ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen.
Provision of mandatory blood samples at screening for central testing using an investigational ctDNA test to be stratified based on PIK3CA/AKT1/PTEN status.
Be eligible for fulvestrant and at least one out of palbociclib or ribociclib (depending on the available CDK4/6i options at time of enrolment), as per local investigator assessment.
Have measurable lesion(s) according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) or, in the absence of measurable disease, lytic or mixed bone lesions that can be assessed by computed tomography (CT) or magnetic resonance imaging (MRI).

Key exclusion criteria for both phases:

History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence.
Radiotherapy within 2 weeks prior to study treatment initiation.
Major surgery or significant traumatic injury within 4 weeks of the first dose of study treatment.
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 or peripheral sensory neuropathy) after consultation with the AstraZeneca study physician.
Spinal cord compression, brain metastases or leptomeningeal metastases unless these lesions are definitively treated (eg. radiotherapy, surgery) and clinically stable off steroids for management of symptoms for at least 4 weeks prior to study treatment initiation.
Any of the following cardiac criteria at screening:

(a). Mean resting corrected QT interval (QTcF): (i) Participants to be treated with palbociclib:: QTcF ≥ 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (ii) Participants to be treated with ribociclib: QTcF ≥ 450 ms obtained from the average of 3 consecutive (triplicate) ECGs (iii) Participants to be treated with abemaciclib (Phase Ib only): QTcF ≥ 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (b). Any clinically important abnormalities in cardiac rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block) (c). Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (d). Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) grade ≥ 2 (e). Uncontrolled hypotension (f) uncontrolled hypertension (g). Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher)

uncontrolled or high grade or symptomatic arrhythmia and atrial fibrillation
Any of these clinically significant abnormalities of glucose metabolism at screening:

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

Key exclusion criteria for the phase III only:

Any prior treatment with, AKT, PI3K or mTOR inhibitors.
Prior treatment with CDK4/6 inhibitors in the metastatic setting (prior CDK4/6 inhibitors permitted in the adjuvant setting provided there was a CDK4/6i treatment free interval of at least 12 months).
More than 1 line of chemotherapy for metastatic disease.
Any line of endocrine-based therapy for inoperable locally advanced or metastatic disease.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation: Randomized
Model: Parallel assignment
Masking: Open label
Primary purpose: Treatment