A Study of Ceralasertib Monotherapy and Ceralasertib Plus Durvalumab in Patients With Melanoma and Resistance to PD-(L)1 Inhibition (MONETTE)

July 21, 2025 updated by: AstraZeneca

A Randomised, Open-Label, Phase 2 Study of Ceralasertib Monotherapy and Ceralasertib Plus Durvalumab in Patients With Unresectable or Advanced Melanoma and Primary or Secondary Resistance to PD-(L)1 Inhibition

Main study: This is an open-label, phase 2 study that aims to evaluate the efficacy and safety/tolerability of ceralasertib, when administered as monotherapy and in combination with durvalumab in participants with unresectable or advanced melanoma and primary or secondary resistance to PD-(L)1 inhibition.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Biopsy sub-study: This is an open-label, non-randomised, sub-study planned in participants suitable for 3 mandatory biopsies. Serial tumour biopsies are mandated in participants recruited into the sub-study and will be taken at baseline during the screening period, during treatment with ceralasertib monotherapy and during the off-treatment period of ceralasertib monotherapy.

Study Type

Interventional

Enrollment (Actual)

194

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Darlinghurst, Australia, 2010
        • Research Site
      • East Melbourne, Australia, 3002
        • Research Site
      • Herston, Australia, 4029
        • Research Site
      • Woolloongabba, Australia, 4102
        • Research Site
  • Belgium
      • Belgium, Belgium, 1200
        • Research Site
      • Bruges, Belgium, 8000
        • Research Site
      • Gent, Belgium, 9000
        • Research Site
      • Leuven, Belgium, 3000
        • Research Site
  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, t6G1Z2
        • Research Site
    • Ontario
      • Toronto, Ontario, Canada, M5G 2M9
        • Research Site
      • Toronto, Ontario, Canada, M4N 3M5
        • Research Site
    • Quebec
      • Ste-Foy, Quebec, Canada, G1V 4G2
        • Research Site
  • France
      • Bobigny, France, 93009
        • Research Site
      • Boulogne Billancourt, France, 92100
        • Research Site
      • Marseille Cedex 5, France, 13385
        • Research Site
      • Paris, France, 75010
        • Research Site
      • Pau Cedex, France, 64046
        • Research Site
      • Pierre-Benite, France, 69310
        • Research Site
      • Poitiers, France, 86021
        • Research Site
      • Vandoeuvre-Les-Nancy, France, 54511
        • Research Site
      • Villejuif Cedex, France, 94805
        • Research Site
  • Germany
      • Berlin, Germany, 10117
        • Research Site
      • Buxtehude, Germany, 21614
        • Research Site
      • Heidelberg, Germany, 69120
        • Research Site
      • Heilbronn, Germany, 74078
        • Research Site
      • Kiel, Germany, 24105
        • Research Site
      • Mainz, Germany, 55131
        • Research Site
      • München, Germany, 80337
        • Research Site
      • Regensburg, Germany, 93053
        • Research Site
      • Schwerin, Germany, 19049
        • Research Site
      • Tuebingen, Germany, D-72076
        • Research Site
  • Italy
      • Candiolo, Italy, 10060
        • Research Site
      • Milan, Italy, 20141
        • Research Site
      • Napoli, Italy, 80131
        • Research Site
      • Padova, Italy, 35128
        • Research Site
      • Perugia, Italy, 06156
        • Research Site
      • Roma, Italy, 00168
        • Research Site
      • Siena, Italy, 53100
        • Research Site
  • Korea, Republic of
      • Goyang, Korea, Republic of, 410-769
        • Research Site
      • Seoul, Korea, Republic of, 03722
        • Research Site
      • Seoul, Korea, Republic of, 05505
        • Research Site
      • Seoul, Korea, Republic of, 06351
        • Research Site
  • Poland
      • Brzozów, Poland, 36-200
        • Research Site
      • Gdańsk, Poland, 80-214
        • Research Site
      • Kraków, Poland, 31-115
        • Research Site
      • Lodz, Poland, 93-513
        • Research Site
      • Poznan, Poland, 60-355
        • Research Site
      • Warszawa, Poland, 02-781
        • Research Site
  • Spain
      • Barcelona, Spain, 08041
        • Research Site
      • Madrid, Spain, 28034
        • Research Site
      • Madrid, Spain, 28040
        • Research Site
      • Madrid, Spain, 28027
        • Research Site
      • Madrid, Spain, 28007
        • Research Site
      • Málaga, Spain, 29009
        • Research Site
      • Pamplona, Spain, 31008
        • Research Site
      • Pozuelo de Alarcon, Spain, 28223
        • Research Site
  • United Kingdom
      • Cambridge, United Kingdom, CB2 0QQ
        • Research Site
      • Chelsea, United Kingdom, SW3 6JJ
        • Research Site
      • Manchester, United Kingdom, M20 4BX
        • Research Site
      • Northwood, United Kingdom, HA6 2RN
        • Research Site
  • United States
    • California
      • Los Angeles, California, United States, 90024
        • Research Site
      • Sacramento, California, United States, 95816
        • Research Site
      • San Francisco, California, United States, 94143
        • Research Site
    • Florida
      • Tampa, Florida, United States, 33612
        • Research Site
    • Maryland
      • Lutherville-Timonium, Maryland, United States, 21093
        • Research Site
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 130 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Participants must have a histologically or cytologically confirmed diagnosis of unresectable or metastatic melanoma of cutaneous, acral or mucosal subtype
  • Availability of an archival tumour sample and a fresh tumour biopsy taken at screening
  • 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.
  • The interval between the last dose of anti-PD-(L)1, BRAF/MEK (B-Rapidly Accelerated Fibrosarcoma gene/mitogen-activated protein kinase gene) inhibitor and the first dose of the study regimen must be a minimum of 14 days
  • Measurable disease by RECIST 1.1.
  • Patients must have a life expectancy ≥3 months from proposed first dose date.
  • Biopsy Sub-study: Consent to the provision of 3 mandatory tumour biopsies.

Exclusion Criteria:

  • Patients must not have experienced a toxicity that led to permanent discontinuation of prior checkpoint inhibitors (CPI) treatment.
  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 3 years before the first dose of study treatment
  • Uveal melanoma
  • Must not have experienced a Grade ≥ 3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy
  • History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study clinical lead.
  • History of organ transplant that requires use of immunosuppressive medications
  • Inadequate bone marrow and impaired hepatic or renal function
  • Known active infection requiring systemic therapy, active hepatitis infection, positive hepatitis C virus antibody, hepatitis B virus (HBV) surface antigen or HBV core antibody (anti-HBc), at screening
  • Patients with confirmed COVID-19 infection by polymearse chain reaction test who have not made a full recovery.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Main study: Ceralasertib + Durvalumab
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.
Drug: Ceralasertib
Ceralasertib (240 mg) will be administered orally twice daily.
Biological: Durvalumab
Durvalumab (1500 mg) will be administered intravenously once every 28 days for participants who weight above > 30 kgs. For participants who weigh below ≤ 30 kgs, weight-based dosing equivalent to 20 mg/kg of durvalumab will be administered.
Experimental: Main study: Ceralasertib
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.
Drug: Ceralasertib
Ceralasertib (240 mg) will be administered orally twice daily.
Experimental: Biopsy Sub-study: Ceralasertib + Durvalumab
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.
Drug: Ceralasertib
Ceralasertib (240 mg) will be administered orally twice daily.
Biological: Durvalumab
Durvalumab (1500 mg) will be administered intravenously once every 28 days for participants who weight above > 30 kgs. For participants who weigh below ≤ 30 kgs, weight-based dosing equivalent to 20 mg/kg of durvalumab will be administered.
Experimental: Biopsy study: Ceralasertib
During Cycle 0, participants will receive ceralasertib on Days 1 to 7, followed by an off-treatment period between Days 8 to 28.
Drug: Ceralasertib
Ceralasertib (240 mg) will be administered orally twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Main Study: Objective Response Rate (ORR)
Time Frame: Cycle 1 Day 1 (Each Cycle is 28 days) until objective disease progression or the last evaluable assessment in the absence of progression, or data cut-off (1 year 8 months)

ORR was defined as the proportion of participants who had a complete response (CR) or partial response (PR) prior to any evidence of progression (as defined by Response Evaluation Criteria in Solid Tumours [RECIST] 1.1) that is confirmed at least 4 weeks later.

As per planned in protocol, this outcome measure was assessed only for main study.
Cycle 1 Day 1 (Each Cycle is 28 days) until objective disease progression or the last evaluable assessment in the absence of progression, or data cut-off (1 year 8 months)
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Center Tumor Region
Time Frame: Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline, on-treatment and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Invasive Margin Region
Time Frame: Baseline, Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Center Tumor Region
Time Frame: Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline, on-treatment and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Invasive Margin Region
Time Frame: Baseline, and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Changes in CD8+ T-cell infiltration of tumours induced by ceralasertib monotherapy was assessed in baseline and off-treatment tumour biopsies As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Main Study and Biopsy Study: Duration of Response (DOR)
Time Frame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first

DOR was defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 or death due to any cause.

For main study BICR data is presented, and for Biopsy sub study, investigator assessment data has been presented.
Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
Main Study and Biopsy Study: Time to Response
Time Frame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first

Time to response was defined as the time from randomization until the date of first documented objective response, which is subsequently confirmed per RECIST 1.1.

For main study blinded independent central review (BICR) data is presented, and for Biopsy sub study, investigator assessment data has been presented.
Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
Main Study and Biopsy Study: Percentage Change From Baseline in Tumour Size
Time Frame: Main Study: at 16 weeks; Biopsy study: at 20 weeks

Percentage change from baseline in target lesion (TL) tumour size was assessed. Tumour size is the sum of the longest diameters of the target lesions. The percentage change from baseline in TL tumour size at post-baseline assessment is obtained for each participants taking the difference between the sum of the TLs at post baseline assessment and the sum of the TLs at baseline divided by the sum of the TLs at baseline times 100. Percentage change from baseline at 16 weeks for main study and 20 weeks for biopsy study in sum of target lesions has been presented.

For main study, BICR data is presented, and for Biopsy sub study, investigator assessment data has been presented.
Main Study: at 16 weeks; Biopsy study: at 20 weeks
Main Study and Biopsy Study: Progression Free Survival (PFS)
Time Frame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first

PFS was defined as time from randomization until progression per RECIST 1.1 or death due to any cause.

For main study BICR data is presented, and for Biopsy sub study, investigator assessment data has been presented.
Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
Main Study and Biopsy Study: Overall Survival (OS)
Time Frame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
OS was defined as time from date of randomization until the date of death due to any cause.
Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
Main Study: Plasma Concentration of Ceralasertib
Time Frame: From Cycle 1 to Cycle 4: Day 7 and Day 8 of each cycle (each cycle is 28 days); 90 days follow-up
Pharmacokinetic (PK) of ceralasertib alone and when in combination with durvalumab was assessed.
From Cycle 1 to Cycle 4: Day 7 and Day 8 of each cycle (each cycle is 28 days); 90 days follow-up
Main Study and Biopsy Study: Number of Participants With Adverse Events (AEs)
Time Frame: From screening (Day -28 to -1) until Safety follow-up (30 days after last dose of Ceralasertib monotherapy or 90 days after last dose of Ceralasertib+Durvalumab combination) or data cut-off (2 years), whichever occurred first

The safety and tolerability of ceralasertib monotherapy and ceralasertib plus durvalumab in participants with unresectable or advanced melanoma and primary or secondary resistance to a programmed death ligand 1 (PD-[L] 1) inhibitor was assessed.

The grading scales found in the revised National Cancer Institute CTCAE latest version was utilized for all events with an assigned CTCAE grading. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 where Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening, urgent intervention required; Grade 5: Death related to AE.
From screening (Day -28 to -1) until Safety follow-up (30 days after last dose of Ceralasertib monotherapy or 90 days after last dose of Ceralasertib+Durvalumab combination) or data cut-off (2 years), whichever occurred first
Biopsy Study: Number of Participants With Presence of PD-L1 Overtime
Time Frame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Pre-treatment presence and/or on-treatment and/or off-treatment changes in PD-L1 was assessed to collect tumour tissue samples, or utilise residual samples, for the analysis of tumoural biomarkers that change following treatment with ceralasertib was assessed.

As per planned in protocol, this outcome measure was assessed only for biopsy study. The number of patients with PD-L1 expression <1% and >= 1% has been presented.
Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Number of Participants With Presence of pRAD50
Time Frame: On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Pre-treatment presence and/or on-treatment and/or off-treatment changes in pRAD50 was assessed to collect tumour tissue samples, or utilise residual samples, for the analysis of tumoural biomarkers that change following treatment with ceralasertib was assessed.

As per planned in protocol, this outcome measure was assessed only for biopsy study.
On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in Proliferation (Using Ki67+ Marker) of Carcinoma and/or Immune Cells (Including CD8+ T Cells) - Cell Density in Center Tumour Region
Time Frame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy was assessed.

As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in Proliferation (Using Ki67+ Marker) of Carcinoma and/or Immune Cells (Including CD8+ T Cells) - Cell Density in Invasive Margin Region
Time Frame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy was assessed.

As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in Proliferation (Using Ki67+ Marker) of Carcinoma and/or Immune Cells (Including CD8+ T Cells) - Area in Centre Tumour Region
Time Frame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy was assessed.

As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Biopsy Study: Change From Baseline in Proliferation (Using Ki67+ Marker) of Carcinoma and/or Immune Cells (Including CD8+ T Cells) - Area in Invasive Margin Region
Time Frame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy was assessed.

As per planned in protocol, this outcome measure was assessed only for biopsy study.
Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AstraZeneca

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2022

Primary Completion (Actual)

April 12, 2024

Study Completion (Estimated)

November 2, 2026

Study Registration Dates

First Submitted

September 22, 2021

First Submitted That Met QC Criteria

September 22, 2021

First Posted (Actual)

September 29, 2021

Study Record Updates

Last Update Posted (Actual)

July 31, 2025

Last Update Submitted That Met QC Criteria

July 21, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D533AC00001
  • 2021-001722-21 (EudraCT Number)
  • 2024-512378-91-00 (Registry Identifier: CTIS)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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