AZD9833 Combinations for Advanced Breast Cancer

(SERENA-1 Trial)

Not currently recruiting at 14 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests AZD9833, an experimental drug for women with advanced breast cancer that is ER-positive and HER2-negative. Researchers aim to evaluate how AZD9833 works alone and in combination with other drugs to determine the best treatment approach for this type of breast cancer. As a Phase 1 trial, it represents an early step in assessing the treatment's safety and effectiveness. Women who have tried other therapies for their advanced breast cancer, which have stopped working or allowed the cancer to grow, might be suitable candidates for this trial. Participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AZD9833, used alone or with other drugs like ribociclib and capivasertib, is generally safe for patients with advanced breast cancer. In studies, AZD9833, also known as camizestrant, was well-tolerated in various combinations.

When combined with ribociclib, AZD9833 proved both effective and safe for patients with ER-positive/HER2-negative breast cancer. Similarly, combining AZD9833 with capivasertib showed a safety profile consistent with each drug individually. Some patients experienced more serious side effects like diarrhea and fatigue, but these were uncommon.

Overall, AZD9833 has been safe in various doses, even when combined with treatments like anastrozole, abemaciclib, palbociclib, and everolimus. Studies have shown that doses of up to 300 mg once daily are safe and well-tolerated.

Although this treatment is still in early testing, these findings suggest that while some risks exist, the safety profile is reassuring based on current data from earlier studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about AZD9833 because it offers a fresh approach to treating advanced breast cancer. Unlike traditional therapies that often target estrogen receptors indirectly, AZD9833 is a new oral selective estrogen receptor degrader (SERD) that aims to directly degrade the estrogen receptor, a key driver in many breast cancers. This direct mechanism could potentially overcome resistance that develops with current treatments like aromatase inhibitors or tamoxifen. Additionally, AZD9833 is being tested in combination with other drugs like ribociclib, abemaciclib, and capivasertib, which might enhance its effectiveness and provide more comprehensive treatment options for patients.

What evidence suggests that this trial's treatments could be effective for advanced breast cancer?

Research has shown that AZD9833, also known as camizestrant, is a promising treatment for ER-positive, HER2-negative advanced breast cancer. Studies indicate that patients taking AZD9833 alone had a median progression-free survival of 7.2 to 7.7 months, during which their cancer did not worsen. In this trial, participants may receive AZD9833 with ribociclib, which has been shown to extend periods without cancer progression and improve response rates. Other participants may receive AZD9833 with capivasertib, which early results suggest could be effective for patients who have already undergone many treatments. Additionally, this trial will explore AZD9833 in combination with other drugs like anastrozole, abemaciclib, palbociclib, and everolimus, all of which have demonstrated strong cancer-fighting effects in previous studies. Overall, AZD9833 shows promise as a safe and effective treatment option for advanced breast cancer when used in various combinations. ^{5 6 7 8 9}

Who Is on the Research Team?

Justin Lindemann, MBChB MBA

Principal Investigator

AstraZeneca

Richard Baird, MD PhD FRCP

Principal Investigator

Breast Cancer Research Unit, University of Cambridge

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)00138-8/fulltext

SERENA-1 monotherapy results Camizestrant (AZD9833) is a next-generation oral SERD and pure ER antagonist, currently in phase III development for treating patients with HR+, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10690091/

The Next-Generation Oral Selective Estrogen Receptor ... Elacestrant has demonstrated modest clinical improvement in median PFS over fulvestrant and AIs in ER+/HER2− advanced breast cancer following treatment with ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.1024

A phase I dose escalation and expansion study of the next ... A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04588298

NCT04588298 | A Study to Investigate the Biological ... The PD effect of AZD9833 on ER expression comparing pre- and on-treatment tumour samples in women with early breast cancer after 5 to 7 days and 12 to 15 days ...

5. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00387-5/abstract

Camizestrant, a next-generation oral SERD, versus ... Median progression-free survival was 7·2 months (90% CI 3·7–10·9) with camizestrant 75 mg, 7·7 months (5·5–12·9) with camizestrant 150 mg, and 3 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04214288

NCT04214288 | A Study to Investigate Efficacy and Safety ... The safety and tolerability of AZD9833 when compared to fulvestrant in women with advanced ER-positive HER2-negative breast cancer was evaluated. From the date ...

7. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D8530C00002

A study to investigate efficacy and safety with oral ... This study is randomized, open-label, parallel-group, multicentre Phase 2 study aimed to compare the efficacy and safety of oral AZD9833 versus intramuscular ( ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03616587

NCT03616587 | Study of AZD9833 Alone or in ... This is a multicentre dose escalation and expansion, first-in-human study designed to evaluate the safety and tolerability of AZD9833, alone (Parts A and B) ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS1101

SERENA-4: A phase 3 comparison of AZD9833 ... A randomized, multicenter, double-blind, phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+ ...