| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| HR positive HER2 negative advanced breast cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase Ib:
To assess the safety and tolerability of capivasertib plus CDK4/6i (palbociclib, ribociclib or abemaciclib) and fulvestrant when dosed concomitantly in participants with advanced breast cancer.
To confirm the recommended Phase III dose (RP3D) and/or maximum tolerated dose (MTD) of the triplets.
Phase III:
To demonstrate the effectiveness of capivasertib plus palbociclib and fulvestrant relative to placebo plus palbociclib and fulvestrant by assessment of PFS in participants with HR+/HER2- locally advanced or metastatic breast cancer (overall population). |
|
| E.2.2 | Secondary objectives of the trial |
Ph Ib: Pharmacokinetics of palbociclib, ribociclib or abemaciclib dosed alone and in combination with capivasertib and fulvestrant. Pharmacokinetics of capivasertib in combination with CDK4/6i and fulvestrant. Effectiveness of capivasertib plus CDK4/6i and fulvestrant when dosed concomitantly by assessment of ORR, CBR, DoR
Ph III: To demonstrate the effectiveness of capivasertib plus palbociclib and fulvestrant relative to placebo plus palbociclib and fulvestrant by assessment of: OS, PFS2, ORR, DoR and CBR in participants with HR+/HER2- locally advanced or metastatic breast cancer (overall population).PFS in participants with HR+/HER2- locally advanced or metastatic breast cancer and gene alterations detected in PIK3CA, AKT1 and/or PTEN.To assess participant reported symptoms, functioning, HRQoL,and overall functional status as well as the safety and tolerability (overall population).To evaluate the PK of capivasertib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. Adequate organ and bone marrow functions.
4. Consent to provide a mandatory FFPE tumour sample.
Inclusion criteria only for phase I:
1. Eligible for fulvestrant therapy and at least one of the following: palbociclib, ribociclib, or abemaciclib, as per local investigator assessment.
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/metastatic setting without progression during the chemotherapy planned course. |
|
| E.4 | Principal exclusion criteria |
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 within 2 weeks prior to study treatment initiation.
3. Major surgical procedure within 4 weeks of the first dose of study treatment.
4. Persistent toxicities (>CTCAE Grade 1) caused by previous anti-cancer therapy, excluding alopecia. Participants with irreversible toxicity expected to be exacerbated by study intervention may be included (eg, hearing loss or peripheral sensory neuropathy) after consultation with the AstraZeneca study physician.
5. Spinal cord compression, brain metastases or leptomeningeal metastases unless these lesions were treated and confirmed stable, asymptomatic and not requiring steroids for the management of the symptoms within 4 weeks prior to study treatment initiation.
6. Any of the following cardiac criteria at screening:
(a). Mean resting corrected QT interval (QTcF): Abemaciclib and palbociclib arms: QTcF ≥ 470 msec obtained from the average of 3 consecutive (triplicate) ECGs
Ribociclib arm: QTcF ≥ 450 msec obtained from the average of 3 consecutive (triplicate) ECGs
(b). Any clinically important abnormalities in rhythm, conduction or morphology of ECG (eg, complete left bundle branch block, second or third-degree AV 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, angina pectoris, congestive heart failure New York Heart Association
(NYHA) grade ≥ 2
(e). Uncontrolled hypotension
(f). Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) unless the condition is considered stable and not clinically significant by the investigator.
7. Any of these clinically significant abnormalities of glucose metabolism at screening:
(a). diabetes mellitus type I or type II requiring insulin treatment
(b). HbA1c ≥ 8.0% (63.9 mmol/mol)
8. Previous allogeneic bone marrow transplant or solid organ transplant.
9. For the phase III: Prior treatment with CDK4/6 inhibitors (in the metastatic setting), a SERD, allosteric mTOR inhibitors, PI3K inhibitors or AKT inhibitors in the metastatic setting. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib:
Safety and tolerability will be evaluated in terms of DLTs, AEs/SAEs, vital signs, clinical chemistry/haematology/glucose metabolism parameters, and ECG parameters.The measures of interest are subject incidence rates, absolute values and change from baseline over time.
Phase III:
PFS is defined as time from randomisation until progression per RECIST v1.1 as assessed by the investigator or death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ib: Assessed at the end of the Phase Ib study and throughout by the Safety Review Committee after each cohort of DLT-evaluable participants have completed Cycle 1 (28 days) or experienced a DLT within cycle one.
Phase III: Up to approximately 33 months from first subject randomised. |
|
| E.5.2 | Secondary end point(s) |
Phase Ib:
1. Palbociclib PK parameters: Cmax, AUC0-72h (Cycle 0), AUC0-24h (Cycle 1), Cmin (Cycle 1); Ribociclib PK parameters: Cmax, AUC0-t (Cycle 0), AUC0-24h (Cycle 1), Cmin (Cycle 1); Abemaciclib PK parameters: Cmax, AUC0-t (Cycle 0), AUC0-12h (Cycle 1), Cmin (Cycle 1)
2. Capivasertib PK parameters: Cmax, AUC0-12h, Cmin
Plasma PK parameters derived from a population PK model, as permitted by the data.
4. ORR
5. CBR at 24 weeks
6. DoR
7. PFS
Phase III:
1. OS
2. PFS in PIK3CA/AKT1/PTEN - altered population
3. PFS2
4. ORR
5. DoR
6. CBR at 24 weeks
7. EORTC QLQ-30 and EORTC QLQ-BR45
8. Time to definitive deterioration.
9. Plasma concentration of capivasertib pre-dose (Ctrough), and post-dose (C1h and C4h) in the
overall population (participants randomised to capivasertib + fulvestrant + palbociclib)
Plasma PK parameters derived from a population PK model, as permitted by the data.
10. Safety and tolerability will be evaluated in terms of AEs/SAEs, vital signs, clinical chemistry/haematology/glucose metabolism parameters, and ECG parameters.
The measures of interest are subject incidence rates, absolute values and change from baseline over time. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase Ib:
At the end of the Phase Ib study.
Phase III:
1. Up to approximately 60 months from first subject randomised
2. Up to approximately 33 months from first subject randomised
3. Up to approximately 60 months from first subject randomised
4. Up to approximately 33 months from first subject randomised
5. Up to approximately 33 months from first subject randomised
6. Up to approximately 33 months from first subject randomised
7. Up to approximately 60 months from first subject randomised
8. Up to approximately 60 months from first subject randomised
9. Up to approximately 33 months from first subject randomised
10. Up to approximately 33 months from first subject randomised |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase Ib: Open, Parallel groups allowed, Phase III: Randomised, double blind |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Phase Ib: not controlled, Phase III: controlled - placebo + SoC |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Malaysia |
| Thailand |
| United States |
| Viet Nam |
| France |
| Poland |
| Sweden |
| Spain |
| Germany |
| Italy |
| Belgium |
| Denmark |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the last visit/contact of the last patient undergoing the study. For phase Ib, there will be a data cutoff defined as the earlier of 6 months after the last patient enrolled starts study treatment, or 30 days after the final patient discontinues treatment. As the phase III is event driven, the accrual of the predetermined number of events included in the study endpoints will determine the duration of the data collection phase of the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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