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AKT inhibition

CompoundCapivasertib

Area under investigation

HR-positive/HER2-negative breast cancer

Scientific PillarTumor Drivers & Resistance Mechanisms

 

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CAPItello-292 trial overview

Tumor

HR+/HER2-negative locally advanced or metastatic breast cancer relapsing on or within 12 months of completing adjuvant ET

Trial Identifier

NCT04862663

Phase

Ib/III

Regimen

Phase Ib - capivasertib + fulvestrant + CDK4/6i (palbociclib or ribociclib or abemaciclib); Phase III - fulvestrant + (palbociclib or ribociclib) ± capivasertib

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Study Design

Inclusion criteria

The key inclusion criteria are –

  • Adult females, pre- and/or post-menopausal and adult males
  • Histologically confirmed locally advanced or metastatic HR+/HER2– BC
  • Eligible for palbociclib, abemaciclib or ribociclib and fulvestrant therapy
  • For phase III only: Previous treatment with ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with radiological evidence of BC recurrence or progression on, or within 12 months of, completing a (neo)adjuvant ET regimen

 

Reference:

Study NCT04862663. ClinicalTrials.gov website.

Exclusion criteria

The key exclusion criteria are –

  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥2 years and of low 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
  • Spinal cord compression or brain metastases unless asymptomatic, treated or stable (not requiring steroids for at least 4 weeks)
  • Clinically significant abnormalities in glucose metabolism
    • Diabetes mellitus type I or type II requiring insulin treatment
    • Glycated hemoglobin (HbA1c) ≥ 8.0% (63.9 mmol/mol)
  • For phase III only:
    a) Prior treatment with PI3K/AKT/mTOR inhibitors, 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)
    b) More than 1 line of chemotherapy for metastatic disease

Study Locator

Explore further trial details, understand eligibility criteria and speak to clinical trial navigators for the CAPItello-292 trial via the Breast Cancer Study Locator website.

Visit Study Locator

CAPItello-292 overview model

CAPItello-292 trial overview

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CAPItello-292 Study Modal

CAPItello-292 trial overview

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Target Overview

The cell signaling network, which includes phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), is frequently dysregulated in human cancer. AKT is a central node in this network, modulating a range of substrates involved in growth, apoptosis, and metabolism. There are 3 isoforms of AKT: AKT1, 2, and 3. The most commonly mutated genes that result in activation of the PI3K/AKT/PTEN pathway are activating mutations of PIK3CA, AKT1 and loss-of-function alterations of PTEN.1,2 

AKT activation has been shown to mediate resistance to inhibitors of receptor tyrosine kinases, antihormonal agents, and chemotherapy.3

Compound Overview

Capivasertib,a a pan-AKT kinase inhibitor (against isoforms AKT1, AKT2, and AKT3), inhibits AKT activity, leading to dephosphorylation of downstream targets. Given the critical position of AKT in this pathway, capivasertib’s mechanism of action serves to restrict the flow of upstream signaling, including that from activating mutations in PIK3CA and loss-of-function PTEN alterations, as well as activating mutations in AKT1 itself, before those can have further downstream effects in driving tumor growth.4-7

aFormerly known as AZD5363, discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited.

Mechanism of Action

  • Mechanism of Action

Reference: Martini M, De Santis MC, Braccini L, et al. Ann Med. 2014;46(6):372-383.

This mechanism of action is depicted for breast cancer cells and is applicable to prostate cancer, where the androgen receptor (AR) plays a role in the nucleus, analogous to the estrogen receptor (ER) in the breast cancer setting. AR pathway blockade with ARPI therapy is the standard-of-care, but inhibiting the AR pathway can result in upregulation of the AKT pathway.8-10

References

1. Altomare DA, Testa JR. Oncogene. 2005;24(50):7455-7464. 2. Liu P, Cheng H, Roberts TM, et al. Nat Rev Drug Discov. 2009;8(8):627-644. 3. Clark AS, West K, Streicher S, et al. Mol Cancer Ther. 2002;1(9):707-717. 4. Davies BR, Greenwood H, Dudley P, et al. Mol Cancer Ther. 2012;11(4):873-887. 5. Miller TW, Rexer BN, Garrett JT, et al. Breast Cancer Res. 2011;13(6):224 6. Miller C, Sommavilla R, Murphy D, et al. Br J Clin Pharmacol 2023;89(11):3330-3339 7. Miricescu D, Totan A, Stanescu-Spinu II, et al. Int J Mol Sci 2020;22(1):173 8. Gasmi A, Roubaud G, Dariane C, et al. J Clin Med. 2021;11:160. 9. Mulholland DJ, Tran LM, Li Y, et al. Cancer Cell. 2011;19:792–804. 10. Carver BS, Chapinski C, Wongvipat J, et al. Cancer Cell. 2011;19:575–586.

 

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CAPItello-292 trial overview

Tumor

HR+/HER2-negative locally advanced or metastatic breast cancer relapsing on or within 12 months of completing adjuvant ET

Trial Identifier

NCT04862663

Phase

Ib/III

Regimen

Phase Ib - capivasertib + fulvestrant + CDK4/6i (palbociclib or ribociclib or abemaciclib); Phase III - fulvestrant + (palbociclib or ribociclib) ± capivasertib

Visit ct.gov

Study Design

Inclusion criteria

The key inclusion criteria are –

  • Adult females, pre- and/or post-menopausal and adult males
  • Histologically confirmed locally advanced or metastatic HR+/HER2– BC
  • Eligible for palbociclib, abemaciclib or ribociclib and fulvestrant therapy
  • For phase III only: Previous treatment with ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with radiological evidence of BC recurrence or progression on, or within 12 months of, completing a (neo)adjuvant ET regimen

 

Reference:

Study NCT04862663. ClinicalTrials.gov website.

Exclusion criteria

The key exclusion criteria are –

  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥2 years and of low 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
  • Spinal cord compression or brain metastases unless asymptomatic, treated or stable (not requiring steroids for at least 4 weeks)
  • Clinically significant abnormalities in glucose metabolism
    • Diabetes mellitus type I or type II requiring insulin treatment
    • Glycated hemoglobin (HbA1c) ≥ 8.0% (63.9 mmol/mol)
  • For phase III only:
    a) Prior treatment with PI3K/AKT/mTOR inhibitors, 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)
    b) More than 1 line of chemotherapy for metastatic disease

Study Locator

Explore further trial details, understand eligibility criteria and speak to clinical trial navigators for the CAPItello-292 trial via the Breast Cancer Study Locator website.

Visit Study Locator

CAPItello-292 overview model

CAPItello-292 trial overview

Take me to ClinicalTrials.Gov

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CAPItello-292 Study Modal

CAPItello-292 trial overview

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Abbreviations

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  • AI

    aromatase inhibitor

  • AKT

    protein kinase B/also known as PKB

  • AR

    androgen receptor

  • BC

    breast cancer

  • BID

    twice daily

  • CBR

    clinical benefit rate

  • CDK4/6

    cyclin-dependent kinase 4/6

  • CDK4/6i

    cyclin-dependent kinase 4/6 inhibitor

  • DoR

    duration of response

  • ET

    endocrine therapy

  • HER2

    human epidermal growth factor receptor 2

  • HR

    hormone receptor

  • HRQoL

    health-related quality of life

  • mTOR

    mechanistic or mammalian target of rapamycin

  • mTPI-2

    modified toxicity probability interval

  • ORR

    overall or objective response rate

  • OS

    overall survival

  • PFS

    progression-free survival

  • PFS2

    time to second progression or death

  • PI3K

    phosphoinositide 3-kinase

  • PIK3CA

    phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

  • PO

    per oral

  • PTEN

    phosphatase and tensin homolog

  • R

    randomization

  • rPFS

    radiographic progression-free survival

  • RTK

    receptor tyrosine kinase

  • SERD

    selective estrogen receptor degrader

Some compounds herein refer to selected AstraZeneca pipeline products still under development. AstraZeneca pipeline products are investigational products and, as such, are not approved by the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or any other regulatory agency for the uses under investigation. Information regarding these investigational products should, under no circumstances, be regarded as a recommendation for their use or of their safety or efficacy.

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Veeva ID: Z4-84958 US-109129 DE-92568 Last Updated October 20263/26
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