Ceralasertib + Durvalumab for Melanoma

(MONETTE Trial)

Not currently recruiting at 84 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants

Disqualifiers: Uveal melanoma, Heart failure, Organ transplant, 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

Compensation: Varies

Number of Visits: 4

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of two treatments, ceralasertib and durvalumab (an immunotherapy drug), for individuals with advanced melanoma that cannot be surgically removed. Researchers aim to determine if these treatments can help when previous therapies targeting PD-(L)1 proteins have failed. Participants will receive either both treatments together or just ceralasertib to assess which is more effective. This trial targets those who have already tried at least one type of immunotherapy for melanoma and experienced progression during treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires a minimum 14-day break from your last dose of anti-PD-(L)1 or BRAF/MEK inhibitors before starting the study treatment. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the study team.

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

Research has shown that the combination of ceralasertib and durvalumab has been tested in patients with advanced cancers. In these studies, about 31% of patients experienced some improvement in their cancer, indicating nearly one-third saw positive changes. Another study found that 63.3% of patients maintained stable disease, meaning their cancer did not worsen.

Ceralasertib alone has generally been safe when used with other cancer drugs, such as paclitaxel, suggesting its safety for humans. When combined with durvalumab, it demonstrated good anti-tumor effects in animal studies, which is promising for human use.

These findings indicate that both ceralasertib and its combination with durvalumab are generally well-tolerated in patients with advanced cancers. However, as the trial is in phase 2, ongoing studies continue to evaluate its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Ceralasertib and Durvalumab for melanoma because they offer a fresh approach compared to existing treatments like immune checkpoint inhibitors and targeted therapies. Ceralasertib is an ATR kinase inhibitor, which means it targets DNA damage repair mechanisms in cancer cells, potentially making them more vulnerable to treatment. Durvalumab, on the other hand, is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. The combination of these two drugs could enhance the overall effectiveness against melanoma by simultaneously disrupting cancer cell repair and boosting the immune response. This dual action approach is what makes these treatments particularly promising.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that the combination of ceralasertib and durvalumab, which participants in this trial may receive, may help treat melanoma. Studies found that about 31% of patients experienced cancer shrinkage or disappearance, and 63.3% had their cancer stop growing temporarily. This indicates that nearly one-third of patients saw their cancer reduce or vanish, while more than half had stable disease for some time. In some studies, patients who had previously tried other immune therapies had their disease controlled for an average of about 5.87 months. In this trial, some participants will receive ceralasertib alone. While some patients responded well to ceralasertib alone, results generally improved when combined with durvalumab. These findings suggest that ceralasertib, especially when used with durvalumab, could be effective for people with advanced melanoma. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma that hasn't responded to PD-(L)1 inhibitors. They should have tried immunotherapy, be expected to live at least 3 more months, and agree to tumor biopsies. People can't join if they've had severe side effects from previous cancer treatments, organ transplants requiring drugs that suppress the immune system, certain heart conditions or infections.

Inclusion Criteria

You have a disease that can be measured according to a specific standard.

I can provide both an old and a new sample of my tumor.

It has been at least 14 days since my last dose of anti-PD-(L)1 or BRAF/MEK inhibitor.

Exclusion Criteria

I have had an organ transplant and take drugs to suppress my immune system.

I have never stopped a CPI treatment due to severe side effects.

I do not have serious heart problems like heart failure, unstable chest pain, or dangerous irregular heartbeats.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive ceralasertib monotherapy or ceralasertib plus durvalumab in 28-day cycles until disease progression or unacceptable toxicity

Up to 2 years

Monthly visits (in-person)

Biopsy Sub-study

Participants undergo mandatory biopsies at baseline, during treatment, and during the off-treatment period

Cycle 1 (28 days)

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Quarterly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ceralasertib
• Durvalumab

Trial Overview The study tests Ceralasertib alone and combined with Durvalumab in patients whose melanoma resisted prior treatment with PD-(L)1 blockers. It's an open-label phase 2 trial aiming to see how well these treatments work and their safety.

How Is the Trial Designed?

Group I: Main study: Ceralasertib + Durvalumab Experimental Treatment 2 Interventions

Participants will receive ceralasertib on Days 1 to 7 plus durvalumab Day 8, once in 28 days (Q28D), until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion is met.

Group II: Main study: Ceralasertib Experimental Treatment 1 Intervention

Participants will receive ceralasertib on Days 1 to 7, Q28D, until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion is met.

Group III: Biopsy study: Ceralasertib Experimental Treatment 1 Intervention

During Cycle 0, participants will receive ceralasertib on Days 1 to 7, followed by an off-treatment period between Days 8 to 28.

Group IV: Biopsy Sub-study: Ceralasertib + Durvalumab Experimental Treatment 2 Interventions

From Cycle 1, participants will receive combination of ceralasertib twice daily (BD) Days 1 to 7 plus durvalumab Day 8, Q28D, until progressive disease, unacceptable toxicity, withdrawal of consent, or a study treatment discontinuation criterion is met.

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

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Durvalumab, an antibody that targets PD-L1, shows antitumor activity as a consolidation therapy for patients with locally advanced unresectable non-small cell lung cancer (NSCLC).

This report presents the first known case of fully reversible bronchiolitis and bronchiectasis induced by durvalumab, challenging the previous belief that such conditions were irreversible following immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab-induced lesions of bronchiolitis and fully reversible bronchiectasis in a patient with non-small cell lung cancer: A case report. Domblides, M., Geier, M., Decroisette, C., et al.[2021]

A 67-year-old male with lung squamous cell carcinoma developed myocarditis after receiving durvalumab, a PD-L1 inhibitor, highlighting the potential for serious cardiac side effects from this treatment.

The patient's myocarditis led to a significant decrease in heart function but improved rapidly with glucocorticoid therapy, suggesting that timely intervention can effectively manage this rare but severe adverse event.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Acute Myocarditis Due to PD-L1 Inhibitor Durvalumab Monotherapy in a Patient With Lung Squamous Cell Carcinoma. Zhou, B., Li, M., Chen, T., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

Durvalumab, used as a consolidation treatment for locally advanced PD-L1-positive non-small cell lung cancer (NSCLC) after chemoradiotherapy, demonstrated comparable efficacy in terms of progression-free survival (20.1 months) and overall survival (not reached) to the results of the PACIFIC trial, even in a more advanced patient population.

The study found that durvalumab is safe and effective in real-world settings, with encouraging outcomes for selected stage IV patients and those with autoimmune diseases, suggesting that PD-L1 status should not exclude patients from receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced unresectable non-small cell lung cancer (NSCLC): Real-world data on survival and safety from the German expanded-access program (EAP). Faehling, M., Schumann, C., Christopoulos, P., et al.[2021]

Durvalumab, an immune checkpoint inhibitor, has shown promising efficacy in treating advanced non-small cell lung cancer (NSCLC) in early phase trials, demonstrating a good safety profile.

The PACIFIC trial has successfully met its primary endpoint, indicating that durvalumab may be an important part of future treatment strategies for NSCLC, with ongoing studies potentially confirming its superiority over current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MEDI 4736 (durvalumab) in non-small cell lung cancer. Jeanson, A., Barlesi, F.[2021]

The combination of MEDI0680 and durvalumab was found to be safe and tolerable in patients with advanced clear-cell renal cell carcinoma, but it did not show improved efficacy compared to nivolumab alone, with objective response rates of 16.7% for the combination and 23.8% for nivolumab.

Both treatment groups had a median progression-free survival of 3.6 months, and a notable percentage of patients (23.8% in the combination group) discontinued treatment due to adverse events, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. Voss, MH., Azad, AA., Hansen, AR., et al.[2023]

Citations

1. nature.com nature.com/articles/s41467-024-45996-4

The ATR inhibitor ceralasertib potentiates cancer ... Here we show that ceralasertib in combination with anti-PD-L1 demonstrates strong antitumor effects in immunocompetent mouse tumor models.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8974415/

Phase I Study of Ceralasertib (AZD6738), a Novel DNA ... In the efficacy set (of 57 patients who received at least one dose of ceralasertib or paclitaxel), there was 1 CR (1.8%, melanoma), 12 confirmed PRs [12/57 (21 ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0923753421045452

Phase II study of ceralasertib (AZD6738) in combination ... Combination treatment resulted in median progression-free survival of 7.1 months and median overall survival of 14.2 months. •. Our data suggest that this ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9258491/

Phase II study of ceralasertib (AZD6738) in combination with ... Among 31 patients, the ORR, disease control rate, median progression-free survival (PFS), and overall survival were 22.6% (95% CI 9.6% to 41.1%) ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.9514

Phase II study of ceralasertib (AZD6738), in combination ... Ceralasertib in combination with durvalumab demonstrated a promising anti-tumor activity, particularly in melanoma patients who failed to standard of care ...

6. esmo.org esmo.org/oncology-news/efficacy-safety-and-translational-data-from-durvalumab-plus-ceralasertib-in-advanced-metastatic-nsclc-following-prior-failure-to-anti-pd1-pd-l1-and-platinum-doublet-therapy

Efficacy, Safety, and Translational Data from Durvalumab ... Greatest clinical benefit was observed with durvalumab plus ceralasertib; objective response rate which was a primary outcome was 13.9% versus ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05061134

NCT05061134 | A Study of Ceralasertib Monotherapy and ... The safety and tolerability of ceralasertib monotherapy and ceralasertib plus durvalumab in participants with unresectable or advanced melanoma and primary ...