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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called capivasertib (also known as TruQap or AZD-5363) to determine if it can shrink or halt cancer growth in patients with an AKT mutation. Capivasertib blocks a protein essential for cancer cell growth. The trial seeks participants with hormone receptor-positive breast cancer that cannot be surgically removed and has progressed despite ongoing hormone therapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that capivasertib is likely to be safe for humans?

Research has shown that capivasertib, also known as AZD5363, has undergone testing in several studies to assess its safety in humans. In these studies, researchers often combined capivasertib with other treatments, such as fulvestrant. Results indicated that participants generally tolerated it well.

A major study with 540 participants examined the safety of capivasertib. It found that while some experienced side effects, most were manageable and not severe. Common side effects included diarrhea and tiredness, typical for many cancer treatments.

Other studies have also shown that capivasertib, when combined with other drugs, can be safely administered to various groups, including premenopausal women. This increases confidence in its safety.

In summary, capivasertib has been studied in many individuals, and findings suggest it is generally safe, with side effects that are usually not too serious. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Capivasertib is unique because it targets a specific signaling pathway in cancer cells known as the AKT pathway, which is often overactive in many cancers. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, capivasertib specifically inhibits this pathway, potentially reducing side effects and sparing healthy cells. Researchers are excited about capivasertib due to its precision in targeting cancer cells and the promise of improved outcomes for patients who may not respond well to existing treatments like chemotherapy or hormone therapy.

What evidence suggests that capivasertib might be an effective treatment for cancer?

Research has shown that capivasertib can help treat certain cancers with changes in the AKT gene. In earlier studies, patients who took capivasertib with fulvestrant experienced longer periods of stable cancer compared to those who only took fulvestrant. This suggests that capivasertib can slow cancer growth. Researchers believe capivasertib works by blocking AKT, a protein essential for cancer cell growth. While these results are promising, the effectiveness can vary depending on the type of cancer and specific genetic changes. ^{1 4 5 6 7}

Who Is on the Research Team?

Kevin M Kalinsky

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37224269/

The efficacy and safety of Capivasertib (AZD5363) in ...

Progression-free survival (PFS) and adverse events (AE) were the primary outcomes. Results: A total of 540 individuals from four RCTs were included.

2.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2214131

Capivasertib in Hormone Receptor–Positive Advanced ...

Capivasertib–fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients ...

3.

truqap.com

truqap.com/about/results-with-truqap

Study Results With TRUQAP® (capivasertib) Tablets

TRUQAP + fulvestrant is proven to give people with HR+/HER2- metastatic breast cancer with abnormal PIK3CA, AKT1, and/or PTEN genes more than twice as long

4.

truqaphcp.com

truqaphcp.com/efficacy

Efficacy | For Healthcare Professionals

TRUQAP + fulvestrant delivered reduction in risk of disease progression or death in patients with PIK3CA, AKT1, or PTEN alterations vs fulvestrant alone.

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7052734/

Fulvestrant plus capivasertib versus placebo after relapse or ...

The results of this study show that the addition of capivasertib to fulvestrant therapy significantly improved progression-free survival in participants with ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01625286

Investigating Safety, Tolerability and Efficacy of AZD5363 ...

The purpose of this study is to investigate the safety and efficacy of different doses and schedules of AZD5363, when in combination with paclitaxel, ...

7.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/nda/2023/218197Orig1s000MultidisciplineR.pdf

NDA/BLA Multi-disciplinary Review and Evaluation

This trial appropriately included premenopausal women, therefore efficacy and safety data of capivasertib plus fulvestrant are now available for this ...