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NCT Number: NCT05061134

A Study of Ceralasertib Monotherapy and Ceralasertib Plus Durvalumab in Patients With Melanoma and 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.

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This study is active but is not currently recruiting participants.

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Key information

Conditions

Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year–130 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Research Site, Darlinghurst, Australia

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Ceralasertib

Drug

Ceralasertib (240 mg) will be administered orally twice daily.

Durvalumab

Biological

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.

Primary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

Sponsors and collaborators

Lead sponsor

AstraZeneca

Industry

Registry information

Official study title

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

Acronym: MONETTE

Important dates

Study start
2022
Primary completion
2024
Study completion
2026
First posted
Sep 29, 2021
Registry last updated
Jul 31, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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