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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Locally Advanced (Inoperable) or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Capivasertib
* Drug: Fulvestrant
* Drug: Palbociclib
* Drug: Ribociclib
* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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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. Inclusion criteria only for phase III: 1. Previous treatment with an ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with: a. radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen 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 . 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase Ib: Open, Parallel groups allowed, recruiting up to approx. 222 participants. Phase III: open-label, randomised, recruiting approx. 628 participants.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capivasertib Plus Palbociclib and Fulvestrant<br>Capivasertib Plus Palbociclib and Fulvestrant (Ph 1b) | Drug: Capivasertib<br>* 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<br>Drug: Fulvestrant<br>* 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<br>Drug: Palbociclib<br>* 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.<br>|
| Experimental: Capivasertib Plus Ribociclib and Fulvestrant<br>Capivasertib Plus Ribociclib and Fulvestrant (Ph 1b) | Drug: Ribociclib<br>* 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.<br>|
| Experimental: Capivasertib Plus Abemaciclib and Fulvestrant<br>Capivasertib Plus Abemaciclib and Fulvestrant (Ph 1b) | Drug: Abemaciclib<br>* Phase Ib: 50 mg/ 100 mg/ 150 mg. Twice daily for 28 consecutive days to comprise a complete 28-day cycle<br>|
| Experimental: Capivasertib Plus Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib)<br>Capivasertib Plus Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib) (Ph III) | Drug: Capivasertib<br>* 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<br>|
| Active Comparator: Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib)<br>Fulvestrant and investigator's choice of CDK4/6i (palbociclib or ribociclib) (Ph III) | Drug: Fulvestrant<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: 1. The number of participants with dose-limiting toxicity, as defined in the protocol. | 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. | Within the first 28 day cycle. | 
| Phase Ib: 2. The number of participants with treatment-related adverse events. | 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. | From baseline up to approximately 36 months. | 
| Phase Ib: 3. The number of participants with treatment-related serious adverse events. | 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. | From baseline up to approximately 36 months. | 
| Phase III: 1. Progression Free Survival (PFS). | Progression Free Survival (PFS) is defined as time from randomization until progression per RECIST v1.1. as assessed by BICR or death due to any cause. RECIST related endpoints such as PFS, ORR, DoR, CBR will be collected | Up to approximately 37 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: 1. PK parameters for Palbociclib, Ribociclib, Abemaciclib: Cmax. | Maximum observed plasma (peak) drug concentration. | 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. | Partial area under the plasma concentration-time curve from zero to 72 hours post-dose. | Cycle 0 (Cycle 0 is 3 days). | 
| Phase Ib: 3. PK parameters for Palbociclib, Ribociclib, Abemaciclib: AUC0-24h. | Partial area under the plasma concentration-time curve from zero to 24 hours post-dose. | 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. | Minimum observed plasma drug concentration. | 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. | Maximum observed plasma (peak) drug concentration. | Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days). | 
| Phase Ib: 6. PK parameters for capivasertib: AUC0-12h. | Partial area under the plasma concentration-time curve from zero to 12 hours post-dose. | Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days). | 
| Phase Ib: 7. PK parameters for capivasertib: Cmin. | Minimum observed plasma drug concentration. | Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days). | 
| Phase Ib: 8. Objective Response Rate (ORR). | 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). | Up to approximately 36 months. | 
| Phase Ib: 9. Clinical Benefit Rate (CBR) at 24 weeks. | 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. | Up to approximately 36 months. | 
| Phase Ib: 10. Duration of Response (DoR). | 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. | Up to approximately 36 months. | 
| Phase Ib: 11. Progression Free Survival (PFS). | 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. | Up to approximately 36 months. | 
| Phase III: 1. Overall Survival (OS). | Overall Survival (OS) - time from randomisation until the date of death due to any cause. | Up to approximately 64 months. | 
| Phase III: 2. Progression Free Survival (PFS) in PIK3CA/ AKT1/ PTEN-altered population. | Progression Free Survival (PFS) - time from randomisation until progression per RECIST v 1.1 as assessed by BICR or death due to any cause. | Up to approximately 37 months. | 
| Phase III: 3. Progression Free Survival 2 (PFS2). | Progression Free Survival (PFS2) - time from randomisation to the earliest of the progression event, after first subsequent therapy or death. | Up to approximately 64 months. | 
| Phase III: 4. Objective Response Rate (ORR). | Objective Response Rate (ORR) - the proportion of patients who have a complete or partial response), as determined by BICR per RECIST v1.1. | Up to approximately 37 months. | 
| Phase III: 5. Duration of Response (DoR). | Duration of Response (DoR) - the time from the date of first documented response until the date of progression per RECIST v1.1 as assessed by BICR, or death due to any cause. | Up to approximately 37 months. | 
| Phase III: 6. Clinical Benefit Rate (CBR) at 24 weeks. | Clinical Benefit Rate (CBR) at 24 weeks-the % of patients who have a CR or PR or who have SD per RECIST v1.1 as assessed by BICR for at least 23 weeks after randomisation. | Up to approximately 37 months. | 
| Phase III: 7. Participant-reported physical functioning | TTD of physical functioning as measured by the physical functioning subscale of the EORTC QLQ-C30. | Up to approximately 64 months. | 
| Phase III: 8. participant-reported GHS/QoL in participants | TTD of GHS/QoL as measured by the GHS/QoL subscale of the EORTC QLQ-C30. | Up to approximately 64 months. | 
| Phase III: 9. Participant-reported overall side effect bother in participants in the capivasertib arm relative to control arm | Proportion of participants experiencing different levels of overall treatment tolerability as measured by the Patient Global Impression-Treatment Tolerability (PGI-TT). | Up to approximately 64 months. | 
| Phase III: 10. Plasma concentration of capivasertib pre- and post-dose. | Plasma concentration of capivasertib pre-, and post-dose. | Up to approximately 64 months. | 
| Phase III: 11. The number of participants with adverse events. | 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. | Up to approximately 64 months. | 
| Phase III: 12. The number of participants with serious adverse events. | 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. | Up to approximately 64 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced (inoperable) or Metastatic Breast Cancer