Phase Ib/III Study of Capivasertib + CDK4/6 Inhibitors + Fulvestrant as Treatment for Advanced/Metastatic HR+/HER2-Breast Cancer (CAPItello-292)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jun 2021 → ongoing

Decision date (initial)

2023-05-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-504997-39-00

EudraCT number

2020-004637-20

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacokinetic, Safety, Pharmacogenetic, Pharmacogenomic, Efficacy, Therapy

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 superiority of the capivasertib arm relative to control arm by assessment of PFS in participants with HR+/HER2- locally advanced or metastatic breast cancer (overall population), and/or, in participants with gene alterations detected in PIK3CA, AKT1 and/or PTEN (altered population), and/or, in participants without gene alterations (confirmed non-altered population).

Secondary objectives 1

1. 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 and PFS in all participants. Ph III: To demonstrate the effectiveness of capivasertib arm (capivasertib and fulvestrant with investigator’s choice of CDK4/6i (either palbociclib or ribociclib) relative to control arm ((fulvestrant + investigator’s choice of CDK4/6i [palbociclib or ribociclib]) by assessment of: OS and ORR (in participants with HR+/HER2- locally advanced or metastatic breast cancer with gene alteration in PIK3CA/AKT1/PTEN - altered population, confirmed non-altered population and overall population), DoR and CBR, PCP-reported physical functioning, GHS/QoL in PCPs with HR+/HER2- locally adv. or MBC (overall population only). Also, to describe PCP-reported overall side effect bother in PCPs in the capivasertib arm relative to control arm. To evaluate the PK of capivasertib. To assess safety and tolerability of the capivasertib arm relative to control arm (overall population).

Conditions and MedDRA coding

Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer

Regulatory references

Scientific advice from competent authorities

U.S. Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002551-PIP01-18

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Key inclusion criteria for both phases: 1. Adult females (pre- and 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 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. 4. Adequate organ and bone marrow functions. 5. Consent to provide a mandatory FFPE tumour sample.
2. Key inclusion criteria only for phase III only: 1. 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. 2. Provision of mandatory blood samples at screening for central testing using an investigational ctDNA test to be stratified based on PIK3CA/AKT1/PTEN status. 3. 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. 4. Have radiologic evidence of recurrence or progression while on, or within 12 months of the end of (neo)adjuvant endocrine treatment (tamoxifen, AI, or oral SERD). 5. 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).

Exclusion criteria 3

1. Key exclusion criteria for both phases: 1. 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. 2. Radiotherapy within 2 weeks prior to study treatment initiation. 3. Major surgery or significant traumatic injury 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 or peripheral sensory neuropathy) after consultation with the AstraZeneca study physician. 5. 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. 6. 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)
2. 7. uncontrolled or high grade or symptomatic arrhythmia and atrial fibrillation 8. Any of these clinically significant abnormalities of glucose metabolism at screening: (a). diabetes mellitus type I or type II requiring insulin treatment (b). Glycated haemoglobin (HbA1c) ≥ 8.0% (63.9 mmol/mol) 9. Previous allogeneic bone marrow transplant or solid organ transplant.
3. Key exclusion criteria for the phase III only: 1. Any prior treatment with AKT, PI3K or mTOR inhibitors. 2. 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). 3. More than 1 line of chemotherapy for metastatic disease 4. Any line of endocrine-based therapy for inoperable locally advanced or metastatic disease.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. Phase III: PFS is defined as time from randomisation until progression per RECIST v1.1 as assessed by BICR, or death due to any cause in the overall population, the altered population, and the confirmed non-altered population.

Secondary endpoints 5

1. 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
2. 3. 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
3. Phase III: For overall population, in altered population and in confirmed non-altered population: 1. OS 2. ORR For overall population only: 3. PFS2 4. DoR 5. CBR at 24 weeks 6. TTD of physical functioning (EORTC QLQ-C30) 7. TTD of GHS/QoL 8. PGI-TT
4. 8. Plasma concentration of capivasertib pre-dose (Ctrough), and post-dose (C1h, C2h, and C4h) in the overall population (participants randomised to Capivasertib)
5. 9. The number of participants with adverse events (data will include clinical observations, ECG parameters, clinical chemistry, hematology, glucose metabolism parameters and vital signs) 10. The number of participants with serious adverse events (data will include clinical observations, ECG parameters, clinical chemistry, hematology, glucose metabolism parameters and vital signs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Locations

8 EU/EEA countries · 70 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 114 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

17 submissions — initial application plus substantial / non-substantial modifications