AZD8421 for Breast and Ovarian Cancer

(CYCAD-1 Trial)

Recruiting at 13 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: CYP3A4/5 inhibitors, Torsades risk drugs

Disqualifiers: Uncontrolled hypertension, Active infections, others

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

Compensation: Varies

Number of Visits: 6

Duration: 6 months

348 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot take any drugs that strongly affect liver enzymes (CYP3A4/5) or have a risk of causing heart rhythm problems (Torsades de Pointes). It's best to discuss your current medications with the trial team to see if any need to be stopped.

What data supports the effectiveness of the drug AZD8421 for breast and ovarian cancer?

Research shows that CDK4/6 inhibitors like abemaciclib, ribociclib, and palbociclib, when combined with endocrine therapy, significantly improve progression-free survival in hormone receptor-positive breast cancer. These drugs are now a standard treatment for this type of cancer, suggesting potential effectiveness for similar treatments like AZD8421. ^{1 2 3 4 5}

Is AZD8421 (Camizestrant) safe for use in humans?

The safety data for CDK4/6 inhibitors like abemaciclib, which is similar to AZD8421, shows that they are generally well-tolerated in humans. Common side effects include diarrhea, infections, and neutropenia (low white blood cell count), but these are manageable. Patient quality of life is maintained during treatment. ^{6 7 8 9 10}

What makes the drug AZD8421 unique for treating breast and ovarian cancer?

AZD8421 is unique because it combines a new treatment with existing CDK4/6 inhibitors like abemaciclib, which are known to help control cancer cell growth by targeting specific proteins involved in cell division. This combination could potentially offer a more effective approach for patients with breast and ovarian cancer, especially those who have not responded well to other treatments. ^{2 3 11 12 13}

What is the purpose of this trial?

This trial is testing a new drug, AZD8421, alone and with other cancer drugs in patients with advanced breast and ovarian cancer who haven't responded well to standard treatments. The goal is to see if it is safe and effective in controlling cancer growth.

Research Team

Richard Baird, MD, PhD

Principal Investigator

Cambridge University Hospitals

Eligibility Criteria

This trial is for adults with advanced breast cancer that's ER+HER2- or metastatic high-grade serious ovarian cancer. Participants must have measurable disease and be able to swallow pills. They should not have had certain treatments before, and their body should be functioning well enough to handle the study drugs.

Inclusion Criteria

I have advanced cancer and have either been treated according to guidelines or a clinical trial is considered my best next treatment option.

My cancer has spread or returned and gotten worse after my last treatment.

I have at least one cancer lesion that can be measured and tracked over time.

Exclusion Criteria

I am not pregnant, breastfeeding, or planning to become pregnant and agree to use effective birth control.

I am not taking drugs that strongly affect liver enzymes and can't stop them for the study.

I don't have severe nausea, vomiting, or major gut surgery that affects medicine absorption.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD8421 alone or in combination with selected targeted anti-cancer drugs to evaluate safety, tolerability, and pharmacokinetics

6 months

Multiple visits at predefined intervals up to Cycle 6

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• AZD8421
• Camizestrant
• CDK4/6 Inhibitor

Trial Overview The study tests AZD8421 alone or combined with other targeted drugs like Palbociclib, Camizestrant, Ribociclib, or Abemaciclib in patients. It aims to find out how safe these treatments are and how well they work against specific types of advanced cancers.

Participant Groups

Group I: Module 2A_ribo Experimental Treatment 3 Interventions

AZD8421 with camizestrant and ribociclib

Group II: Module 2A_palbo Experimental Treatment 3 Interventions

AZD8421 with camizestrant and palbociclib

Group III: Module 2A_abema Experimental Treatment 3 Interventions

AZD8421 with camizestrant and abemaciclib

Group IV: Module 1 Experimental Treatment 1 Intervention

AZD8421 monotherapy

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Palbociclib has been approved for treating hormone receptor-positive advanced breast cancer due to its ability to improve progression-free survival when used with endocrine agents, highlighting its efficacy in this patient population.

Abemaciclib and ribociclib, two other CDK4/6 inhibitors, are in late-stage clinical development and may offer different benefits, such as single-agent activity and central nervous system penetration, which could influence treatment choices and patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Barroso-Sousa, R., Shapiro, GI., Tolaney, SM.[2020]

The addition of CDK4 and 6 inhibitors (like abemaciclib, palbociclib, or ribociclib) to endocrine therapy significantly improves progression-free survival and response rates in patients with HR+ and HER2- metastatic breast cancer, establishing these inhibitors as a new standard of care.

Exploratory analyses suggest that abemaciclib may be particularly beneficial for women with poor prognosis indicators, although further confirmation is needed for these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. Martin, M., Garcia-Saenz, JA., Manso, L., et al.[2021]

In a phase 1b study involving 50 patients with advanced non-small cell lung cancer (NSCLC), the combination of abemaciclib and pembrolizumab showed significant toxicity, with 80% of patients in cohort A and 76% in cohort B experiencing severe treatment-emergent adverse events.

Despite some antitumor activity, including a disease control rate of 56% in cohort A and 64% in cohort B, the overall risk-benefit profile of this combination therapy does not support further investigation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. Pujol, JL., Vansteenkiste, J., Paz-Ares Rodríguez, L., et al.[2022]

Abemaciclib, when added to standard endocrine therapy, significantly reduces the risk of invasive disease and distant recurrence in high-risk early breast cancer patients, showing a 30% reduction in risk and improved invasive disease-free survival at 15.5 months and 27 months.

Over 80% of patients experienced diarrhea as a side effect, highlighting the need for monitoring and management of this adverse effect during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer. Raheem, F., Ofori, H., Simpson, L., et al.[2022]

In a phase I trial involving 26 Chinese patients with advanced cancers, abemaciclib was found to be well tolerated, with most treatment-emergent adverse events being mild (Grade 1 or 2), although 32% experienced neutropenia and 24% experienced thrombocytopenia.

The pharmacokinetic profile showed slow absorption and a half-life of about 24 hours, with a disease control rate of 68%, indicating preliminary antitumor activity, although no complete responses were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase I Study of Abemaciclib in Chinese Patients with Advanced and/or Metastatic Cancers. Zhang, J., Yang, N., Ji, D., et al.[2021]

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) significantly improve progression-free survival in patients with hormone receptor-positive HER2-negative metastatic breast cancer when used alongside endocrine therapy, with a consistent hazard ratio of around 0.5 across phase III trials.

These treatments are generally well tolerated, with manageable side effects; however, abemaciclib is associated with a higher incidence of diarrhea, while palbociclib and ribociclib are more likely to cause hematological toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. Eggersmann, TK., Degenhardt, T., Gluz, O., et al.[2019]

Abemaciclib, a recently approved CDK4/6 inhibitor, is effective for treating hormone-receptor-positive breast cancer, which is the most common subtype of breast cancer.

The oral administration and manageable side effects of abemaciclib make it a favorable option for patients, highlighting its potential role in both current and future breast cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of abemaciclib and its potential in the treatment of breast cancer. Martin, JM., Goldstein, LJ.[2020]

In a study of 396 female patients with hormone receptor positive, HER2-negative metastatic breast cancer receiving CDK4 and 6 inhibitors, the most common adverse events were neutropenia, diarrhea, and fatigue, with varying frequencies depending on the specific drug used.

The study found that while the overall incidence of adverse events was lower than in clinical trials, the rates of dose reductions and treatment holds due to these events were higher, suggesting that clinicians may be actively managing side effects to help patients continue their therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting. Price, GL., Sudharshan, L., Ryan, P., et al.[2022]

In the nextMONARCH study involving women with endocrine-refractory HR+, HER2- metastatic breast cancer, abemaciclib showed a median progression-free survival (PFS) of 9.1 months when combined with tamoxifen, but this was not significantly better than the 7.4 months PFS with abemaciclib alone plus prophylactic loperamide.

The study found that the incidence and severity of diarrhea, a common side effect of abemaciclib, were manageable with dose adjustments and antidiarrheal medication, indicating that the treatment can be tolerated while maintaining its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer. Hamilton, E., Cortes, J., Ozyilkan, O., et al.[2021]

In a Phase 1b study involving 67 women with hormone receptor positive (HR+) and HER2 negative metastatic breast cancer, abemaciclib combined with endocrine therapies showed a median progression-free survival of 25.4 months and an objective response rate of 38.9%.

The treatment was generally well-tolerated, with manageable side effects such as diarrhea and fatigue, and no significant impact on the pharmacokinetics of the endocrine therapies used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study. Tolaney, SM., Beeram, M., Beck, JT., et al.[2022]

Abemaciclib is a potent oral CDK4 and CDK6 inhibitor that effectively treats hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, showing response rates between 19.7% and 59% in major clinical trials.

The drug is well-tolerated, with common side effects including diarrhea and neutropenia, and it offers the advantage of continuous dosing and potential use as a monotherapy, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer. Palumbo, A., Lau, G., Saraceni, M.[2020]

Abemaciclib, a CDK 4/6 inhibitor, offers a continuous dosing schedule and a different toxicity profile compared to other inhibitors like palbociclib and ribociclib, showing similar clinical benefits in treating ER+/HER2- advanced metastatic breast cancer.

The ongoing MONARCH-E trial may reveal the potential of abemaciclib in early-stage treatment, particularly for high-risk patients, while emerging biomarker research could help identify which tumors respond best to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib, a potent cyclin-dependent kinase 4 and 6 inhibitor, for treatment of ER-positive metastatic breast cancer. Lee, KA., Shepherd, ST., Johnston, SR.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. [2020]

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

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. [2021]

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

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. [2022]

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

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer. [2022]

5. France pubmed.ncbi.nlm.nih.gov

A Randomized Phase I Study of Abemaciclib in Chinese Patients with Advanced and/or Metastatic Cancers. [2021]

6. France pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Profile of abemaciclib and its potential in the treatment of breast cancer. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting. [2022]

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

nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study. [2022]

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

Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Abemaciclib, a potent cyclin-dependent kinase 4 and 6 inhibitor, for treatment of ER-positive metastatic breast cancer. [2020]