What side effects are associated with this type of intervention?

Ceralasertib, an ATR kinase inhibitor, and durvalumab, a PD-L1 inhibitor, are being studied for their efficacy in treating melanoma. Common side effects of PD-L1 inhibitors like durvalumab include skin reactions, endocrine events, and immune-related adverse effects such as pneumonitis, colitis, hepatitis, and nephritis. For ATR kinase inhibitors like ceralasertib, side effects may include hematologic toxicities, gastrointestinal disturbances, and fatigue. Combination therapies often increase the risk and severity of these adverse effects, necessitating careful monitoring and management.

What prior FDA approvals exist?

The FDA has approved several immune checkpoint inhibitors for the treatment of melanoma, including pembrolizumab and nivolumab, which target PD-1, and ipilimumab, which targets CTLA-4. These drugs have shown significant efficacy in treating advanced melanoma. Additionally, combination therapies such as nivolumab plus ipilimumab have been approved for their enhanced effectiveness. While ceralasertib (an ATR kinase inhibitor) is still under investigation, durvalumab (a PD-L1 inhibitor) is similar to other approved PD-1/PD-L1 inhibitors like pembrolizumab and nivolumab, which have become standard treatments for melanoma.

What other types of research exist?

Promising novel alternatives for melanoma treatment in 2024 include: 1) Pembrolizumab (PD-1 inhibitor) combined with other agents like cetuximab (EGFR inhibitor), which has shown efficacy in other cancers and is being investigated for melanoma. 2) Farnesyltransferase inhibitors like tipifarnib, which have demonstrated significant response rates in other cancers and may offer a new approach for melanoma. 3) Novel combination therapies involving metronomic chemotherapy with low-dose nivolumab, which target tumor angiogenesis and immune checkpoints. These alternatives represent innovative approaches that could be effective for melanoma patients.

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Protein Kinase Inhibitor

Ceralasertib + Durvalumab for Melanoma (MONETTE Trial)

Phase 2

Waitlist Available

Research Sponsored by AstraZeneca

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants must have a histologically or cytologically confirmed diagnosis of unresectable or metastatic melanoma of cutaneous, acral or mucosal subtype

Patient must have received at least 1 prior immunotherapy (anti-PD-(L)1 ± anti-CTLA-4 [Cytotoxic T-lymphocyte-associated protein 4]) for a minimum of 6 weeks and no more than 2 prior regimens in the metastatic setting. Patients must have confirmed progression during treatment with a PD-(L)1 inhibitor +/- a CTLA-4 inhibitor.

Must not have

History of organ transplant that requires use of immunosuppressive medications

Patients must not have experienced a toxicity that led to permanent discontinuation of prior checkpoint inhibitors (CPI) treatment.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from screening until death (approx. up to 2 years)

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug for people with melanoma that has spread or can't be removed surgically, and who have already tried a different kind of treatment.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Ceralasertib may cause blood cell count changes, liver enzyme alterations leading to potential liver damage, fatigue, nausea and rash. Durvalumab might lead to immune-related issues affecting organs like lungs or intestines (pneumonitis or colitis), skin problems (rash), hormone gland disorders (thyroid issues), and infusion reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My melanoma cannot be removed by surgery and is of a specific type (skin, acral, or mucosal).

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I've had 1-2 treatments with specific immune therapies for my advanced cancer and it has progressed despite these treatments.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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

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I tested positive for COVID-19 and haven't fully recovered.

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My liver, kidneys, or bone marrow are not working well.

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I have been diagnosed with uveal melanoma.

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I haven't had severe side effects from previous immunotherapy.

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I do not have an active infection or hepatitis that needs treatment.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from screening until death (approx. up to 2 years)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from screening until death (approx. up to 2 years)

This trial's timeline: 3 weeks for screening, Varies for treatment, and from screening until death (approx. up to 2 years) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Biopsy sub-study: CD8+ T-cells tumour infiltration assessed in baseline, on-treatment and off-treatment tumour biopsies

Main study: Objective response rate (ORR)

Secondary study objectives

Biopsy sub-study: Assessment of proliferation of carcinoma in Ki67 marker (Marker Of Proliferation Ki-67) or CD8+ T cells immune cells

Biopsy sub-study: ORR

Biopsy sub-study: Pre-treatment presence and/or on-treatment and/or off-treatment changes in PD-L1 and pRAD50

+7 more

Side effects data

From 2022 Phase 3 trial • 867 Patients • NCT03084471

26%

Asthenia

20%

Anaemia

20%

Constipation

17%

Decreased appetite

16%

Diarrhoea

15%

Nausea

13%

Pruritus

10%

Urinary tract infection

10%

Cough

10%

Fatigue

Vomiting

Dyspnoea

Back pain

Oedema peripheral

Pyrexia

Arthralgia

Hypothyroidism

Haematuria

Abdominal pain

Blood creatinine increased

Weight decreased

Sepsis

Tumour hyperprogression

General physical health deterioration

Pneumonia

Death

Acute kidney injury

Pyelonephritis

Device related infection

Urosepsis

Pulmonary embolism

100%

80%

60%

40%

20%

Study treatment Arm

Durvalumab

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

4Treatment groups

Experimental Treatment

Group I: Main study: Ceralasertib + DurvalumabExperimental Treatment2 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: CeralasertibExperimental Treatment1 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: CeralasertibExperimental Treatment1 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 + DurvalumabExperimental Treatment2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Durvalumab

2017

Completed Phase 2

~3750

Ceralasertib

2017

Completed Phase 1

~40

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Ceralasertib, an ATR kinase inhibitor, targets the ATR protein involved in DNA damage response, preventing cancer cells from repairing their DNA and leading to cell death. Durvalumab, a PD-L1 inhibitor, blocks the interaction between PD-L1 on tumor cells and PD-1 on T-cells, enhancing the immune system's ability to attack cancer cells. These mechanisms are crucial for melanoma patients as they target both the tumor's repair mechanisms and enhance the body's immune response, potentially leading to more effective treatments.