Capivasertib for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Fulvestrant, Aromatase inhibitors, GnRH agonists

Must not be taking: SERMs, CYP3A4 inhibitors

Disqualifiers: KRAS, NRAS, HRAS, BRAF, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: Up to 3 years

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests capivasertib, a drug that blocks a protein needed for cancer cell growth, in patients with advanced cancers that have an AKT mutation. Researchers hope it will shrink or stop the growth of these cancers. Capivasertib has shown effectiveness when used with other treatments for different types of breast cancer.

Will I have to stop taking my current medications?

The trial allows some patients with certain types of breast cancer to continue taking specific medications like fulvestrant or aromatase inhibitors (e.g., letrozole) if they were already on them. However, you cannot take medications like tamoxifen or any strong inhibitors or inducers of certain enzymes (CYP3A4 or CYP2D6) within 2 weeks before starting the trial.

What data supports the effectiveness of the drug Capivasertib for cancer?

Research shows that Capivasertib can help stabilize or shrink tumors in patients with certain genetic mutations in their cancer. It has shown promise in treating breast cancer and prostate cancer when used with other medications. ^{1 2 3 4 5}

What makes the drug capivasertib unique for cancer treatment?

Capivasertib is unique because it is a pan-AKT inhibitor, meaning it targets all three forms of the AKT enzyme, which is involved in cancer cell growth. This drug has shown promise in stabilizing or shrinking tumors with specific genetic mutations, such as AKT1 mutations, and is being studied in combination with other treatments for breast cancer. ^{1 3 4 6 7}

Research Team

Kevin M Kalinsky

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for cancer patients with a specific genetic change called AKT mutation. It's open to those who've met previous MATCH Protocol criteria, have certain types of breast cancer, and are not on strong CYP3A4 or CYP2D6 inhibitors. People with diabetes can join if their condition is under control without insulin or multiple medications.

Inclusion Criteria

My recent ECG showed no significant heart issues.

My breast cancer is hormone receptor positive, HER2 negative, and has not been removed by surgery.

I have diabetes or am at risk but my fasting glucose is under 160 mg/dL, I don't use insulin, and I take two or fewer diabetes pills.

Exclusion Criteria

I am not allergic to AZD5363 or similar medications.

My cancer does not have KRAS, NRAS, HRAS, or BRAF mutations.

I haven't taken PI3K, AKT, or mTOR inhibitors for my cancer, except for short trials or approved rapalogs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive capivasertib (AZD5363) orally twice daily on specified days in 28-day cycles

Up to 3 years

Visits every 2 cycles for the first 26 cycles, then every 3 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 3 months if less than 2 years from study entry, then every 6 months for year 3

Treatment Details

Interventions

• Capivasertib

Trial Overview Researchers are testing AZD5363 in this phase II trial to see if it can shrink cancers or stop them from growing by blocking the AKT protein. The study focuses on patients whose cancers have an AKT mutation.

Participant Groups

Group I: Treatment (capivasertib) Experimental Treatment 1 Intervention

Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Capivasertib is already approved in United States, European Union for the following indications:

Approved in United States as Truqap for:

• Hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations

Approved in European Union as Truqap for:

• Locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Capivasertib significantly improved progression-free survival (PFS) and overall survival (OS) in patients with solid tumors, showing a hazard ratio (HR) of 0.75 for PFS and 0.61 for OS in the overall population of 540 individuals from four randomized controlled trials (RCTs).

While Capivasertib demonstrated promising antitumor efficacy, it was associated with a higher rate of treatment discontinuation due to adverse events compared to placebo, indicating the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of Capivasertib (AZD5363) in the treatment of patients with solid tumor: a systematic review and meta-analysis of randomized clinical trials. Abushanab, AK., Mousa, MT., Mustafa, MT., et al.[2023]

AZD5363, a pan-AKT inhibitor, shows promising efficacy in treating triple-negative metastatic breast cancer, especially in patients with specific genetic alterations, as indicated by a study involving 28 patient-derived xenografts (PDXs).

The study identified key biomarkers for sensitivity to AZD5363, such as mutations in PIK3CA/AKT1, and revealed mechanisms of resistance, including cyclin D1 overexpression, which could help tailor more effective treatments for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Gris-Oliver, A., Palafox, M., Monserrat, L., et al.[2021]

In the FAKTION trial involving 140 postmenopausal women with advanced breast cancer, the addition of capivasertib to fulvestrant significantly improved progression-free survival, with a median of 10.3 months compared to 4.8 months for the placebo group, indicating its efficacy in this patient population.

While capivasertib showed promising results, it was associated with serious adverse events, including acute kidney injury and infections, highlighting the need for careful monitoring and further investigation in phase 3 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Jones, RH., Casbard, A., Carucci, M., et al.[2021]

In a phase II trial involving 150 patients with metastatic castration-resistant prostate cancer (mCRPC), the addition of capivasertib to standard chemotherapy did not significantly prolong composite progression-free survival (cPFS) compared to placebo, with median cPFS of 7.03 months for capivasertib versus 6.70 months for placebo.

However, capivasertib was associated with a significant improvement in overall survival (OS), with a median OS of 31.15 months for the capivasertib group compared to 20.27 months for the placebo group, suggesting potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). Crabb, SJ., Griffiths, G., Marwood, E., et al.[2022]

Capivasertib, an oral AKT inhibitor, was well tolerated when combined with weekly paclitaxel in patients with advanced ER+/HER2- breast cancer, with a recommended dosing schedule of 400 mg twice daily for 4 days on and 3 days off.

However, the addition of capivasertib did not significantly improve progression-free survival compared to placebo, with median PFS of 10.9 months for capivasertib versus 8.4 months for placebo in the overall population, indicating it may not enhance treatment outcomes in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Turner, NC., Alarcón, E., Armstrong, AC., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Capivasertib Active against AKT1-Mutated Cancers. [2019]

2. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of Capivasertib (AZD5363) in the treatment of patients with solid tumor: a systematic review and meta-analysis of randomized clinical trials. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). [2022]

6. England pubmed.ncbi.nlm.nih.gov

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT). [2022]