AZD9833 Combinations for Advanced Breast Cancer

(SERENA-1 Trial)

Recruiting at 13 trial locations

Overseen By AZ Breast Cancer Study Navigators AZ Breast Cancer Study Navigators

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must be taking: LHRH agonists

Must not be taking: CYP3A4 inhibitors, QT prolonging drugs

Disqualifiers: Uncontrolled hypertension, Diabetes, others

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

Compensation: Varies

Number of Visits: 12

Duration: 16 weeks

396 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a washout period for certain medications: 6 months for fulvestrant and 4 months for tamoxifen. Additionally, you cannot take medications that strongly affect certain liver enzymes or drugs that prolong the QT interval. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug AZD9833 for advanced breast cancer?

The research highlights the potential of combination targeted therapies and endocrine therapy for treating metastatic breast cancer, which is similar to the approach being investigated with AZD9833. These therapies have shown significant clinical benefits in managing hormone receptor positive tumors, which are common in breast cancer. ^{1 2 3 4 5}

What safety data exists for AZD9833 or similar treatments?

AZD9496, a treatment similar to AZD9833, was generally well tolerated in a study with women who had advanced breast cancer. Common side effects included diarrhea, fatigue, and nausea, but these were mostly mild and reversible. ^{6 7 8 9 10}

What makes the drug AZD9833 unique for advanced breast cancer?

AZD9833 is a novel treatment for advanced breast cancer that may offer a new approach compared to existing therapies. While traditional treatments often focus on chemotherapy or targeting the HER2 protein, AZD9833 is being explored in combination with other targeted therapies, potentially providing a different mechanism of action or improved outcomes for patients. ^{3 4 11 12 13}

What is the purpose of this trial?

A Phase 1 Dose Escalation and Expansion Study of AZD9833 Alone or in Combination in Women with ER Positive, HER2 Negative Advanced Breast Cancer (SERENA-1)

Research Team

Richard Baird, MD PhD FRCP

Principal Investigator

Breast Cancer Research Unit, University of Cambridge

Justin Lindemann, MBChB MBA

Principal Investigator

AstraZeneca

Eligibility Criteria

This trial is for women with advanced breast cancer that's ER positive and HER2 negative. They must be over 18, have had no more than two chemo treatments for advanced disease, and not be on certain drugs or have specific health issues like uncontrolled hypertension or severe systemic diseases. Participants need to agree to contraception if of childbearing potential.

Inclusion Criteria

My cancer has spread or returned and doesn't respond to current treatments.

My cancer is estrogen receptor positive.

My cancer is not HER2 positive.

Exclusion Criteria

I do not have severe illnesses like uncontrolled high blood pressure, active bleeding disorders, or infections like hepatitis or HIV.

My heart's pumping ability is below normal, or I've had specific heart procedures or conditions in the last 6 months.

My blood pressure is not controlled by medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD9833 alone or in combination with other drugs to evaluate safety and tolerability

16 weeks

Regular visits at predefined intervals

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 1 year

Visits every 12 weeks

Treatment Details

Interventions

• AZD9833

Trial Overview The study tests AZD9833 alone or combined with other drugs (capivasertib, abemaciclib, ribociclib, anastrozole, palbociclib, everolimus) in different groups to find the best treatment for this type of breast cancer. It's a Phase 1 trial focusing on dosage safety and effectiveness.

Participant Groups

Group I: AZD9833 with ribociclib (± anastrozole) dose expansion Experimental Treatment 1 Intervention

Group II: AZD9833 with ribociclib (± anastrozole) dose escalation Experimental Treatment 1 Intervention

Group III: AZD9833 with palbociclib dose expansion Experimental Treatment 1 Intervention

Group IV: AZD9833 with palbociclib dose escalation Experimental Treatment 1 Intervention

Group V: AZD9833 with everolimus dose expansion Experimental Treatment 1 Intervention

Group VI: AZD9833 with everolimus dose escalation Experimental Treatment 1 Intervention

Group VII: AZD9833 with capivasertib dose expansion Experimental Treatment 1 Intervention

Group VIII: AZD9833 with capivasertib dose escalation Experimental Treatment 1 Intervention

Group IX: AZD9833 with anastrozole dose expansion Experimental Treatment 1 Intervention

Group X: AZD9833 with anastrozole dose escalation Experimental Treatment 1 Intervention

Group XI: AZD9833 with abemaciclib (± anastrozole)dose expansion Experimental Treatment 1 Intervention

Group XII: AZD9833 with abemaciclib (± anastrozole) dose escalation Experimental Treatment 1 Intervention

Group XIII: AZD9833 monotherapy dose expansion Experimental Treatment 1 Intervention

Group XIV: AZD9833 monotherapy dose escalation Experimental Treatment 1 Intervention

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

AZD9496, an oral inhibitor of estrogen receptor alpha, was found to be well tolerated in a phase I study involving 45 women with advanced ER+/HER2- breast cancer, with common side effects including diarrhea, fatigue, and nausea.

The study showed preliminary signs of antitumor activity, with one patient achieving a partial response and four others maintaining stable disease for up to 12 months, indicating potential effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer. Hamilton, EP., Patel, MR., Armstrong, AC., et al.[2019]

AZD5363, an oral medication for advanced solid tumors, showed a more tolerable safety profile with intermittent dosing compared to continuous dosing, leading to a recommended dose of 480 mg twice daily on a 4 days on, 3 days off schedule.

Preliminary results indicated antitumor activity, particularly in patients with the Akt1 (E17K) mutation, suggesting that this mutation may help predict which patients are more likely to respond to AZD5363 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. Tamura, K., Hashimoto, J., Tanabe, Y., et al.[2019]

The combination of ZD9331 and cisplatin was well tolerated at a dose of 130/50 mg/m², with dose-limiting toxicities including neutropenia and thrombocytopenia, indicating a manageable safety profile for this regimen.

Among the 15 patients evaluated, 2 experienced a partial response to treatment, and 6 had stable disease, suggesting that this combination therapy may have preliminary antitumor activity in patients with refractory solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies. Bilenker, JH., Stevenson, JP., Flaherty, KT., et al.[2013]

The Phase II MINT study involving 359 patients found that adding AZD8931 to anastrozole did not significantly improve progression-free survival compared to anastrozole alone, with median PFS being similar across treatment groups.

Patients receiving AZD8931 experienced higher rates of gastrointestinal and skin-related side effects, such as diarrhea and rash, indicating that while AZD8931 was safe, it did not provide additional therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of EGFR, HER2, and HER3 signaling with AZD8931 in combination with anastrozole as an anticancer approach: Phase II randomized study in women with endocrine-therapy-naïve advanced breast cancer. Johnston, S., Basik, M., Hegg, R., et al.[2018]

AZD3409 demonstrated significant antineoplastic activity in breast and ovarian cancer cell lines, with varying IC50 concentrations indicating its effectiveness at different doses: 19.16 µM for MDA-MB-231 and 3.19 µM for A2780.

The mechanism of action for AZD3409 includes the inhibition of farnesylation of HDJ-2, which contributes to its cytotoxic effects, alongside differential impacts on growth factor secretion and Akt activation in breast versus ovarian cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulation of tumor signaling pathways by AZD3409 in vitro. Streeper, R., Campos, D., Carrizales, G., et al.[2007]

HER2-positive breast cancer, which historically had a poor prognosis, can now be effectively treated with a variety of anti-HER2 therapies, significantly improving patient survival rates.

Newly developed treatments, including trastuzumab deruxtecan and trastuzumab emtansine, along with ongoing clinical trials, are expanding options for patients with advanced HER2-positive breast cancer, raising important questions about the best treatment sequences and combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. Stanowicka-Grada, M., Senkus, E.[2023]

Chemotherapy, particularly with taxoids like docetaxel and paclitaxel, shows significant activity against metastatic breast cancer, but overall survival rates remain disappointing, indicating a need for better treatment options.

Recent trials suggest that high-dose chemotherapy may lead to higher complete response rates and potential survival benefits compared to traditional dosing, highlighting the importance of ongoing research into new treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimising treatment outcomes: a review of current management strategies in first-line chemotherapy of metastatic breast cancer. Crown, J.[2019]

Paclitaxel has shown high effectiveness in treating advanced breast cancer, including cases resistant to anthracyclines, prompting research into its combination with anthracyclines like doxorubicin.

Clinical trials of the paclitaxel/doxorubicin combination have reported promising response rates, although the toxicity profiles vary significantly based on the administration schedule used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and doxorubicin in metastatic breast cancer. Gehl, J., Boesgaard, M., Paaske, T., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. [2020]

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

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer. [2022]

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

Choosing the appropriate breast cancer therapy for today's breast cancer patient. [2018]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of metastatic breast cancer: looking towards the future. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Optimal management of hormone receptor positive metastatic breast cancer in 2016. [2022]

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

A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies. [2013]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Inhibition of EGFR, HER2, and HER3 signaling with AZD8931 in combination with anastrozole as an anticancer approach: Phase II randomized study in women with endocrine-therapy-naïve advanced breast cancer. [2018]

10. Greece pubmed.ncbi.nlm.nih.gov

Regulation of tumor signaling pathways by AZD3409 in vitro. [2007]

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

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Optimising treatment outcomes: a review of current management strategies in first-line chemotherapy of metastatic breast cancer. [2019]

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

Paclitaxel and doxorubicin in metastatic breast cancer. [2015]