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

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

Status

Active, not recruiting

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05061134

Acronym

MONETTE

Enrollment

194

Registered

2021-09-29

Start date

2022-08-11

Completion date

2026-11-02

Last updated

2025-07-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma

Keywords

Unresectable or Advanced Melanoma, Efficacy, Safety

Brief summary

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.

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.

Interventions

DRUGCeralasertib

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

BIOLOGICALDurvalumab

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Main Study: Objective Response Rate (ORR)	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.
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Center Tumor Region	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.
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Invasive Margin Region	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.
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Center Tumor Region	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.
Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Invasive Margin Region	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

Measure	Time frame	Description
Main Study: Plasma Concentration of Ceralasertib	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.
Main Study and Biopsy Study: Number of Participants With Adverse Events (AEs)	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.
Biopsy Study: Number of Participants With Presence of PD-L1 Overtime	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.
Biopsy Study: Number of Participants With Presence of pRAD50	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.
Main Study and Biopsy Study: Duration of Response (DOR)	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.
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	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.
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	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.
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	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.
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	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.
Main Study and Biopsy Study: Time to Response	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.
Main Study and Biopsy Study: Percentage Change From Baseline in Tumour Size	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 and Biopsy Study: Progression Free Survival (PFS)	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.
Main Study and Biopsy Study: Overall Survival (OS)	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.

Countries

Australia, Belgium, Canada, France, Germany, Italy, Poland, South Korea, Spain, United Kingdom, United States

Participant flow

Recruitment details

This study was conducted between 11 Aug 2022 (first participants enrolled) to 12 Apr 2024 (primary completion date). The study was conducted in 11 countries.

Pre-assignment details

Participants who met the inclusion criteria and none of the exclusion criteria were enrolled to the study. Informed consent forms (ICFs) was signed prior to screening procedures. All study assessments were performed as per the Schedule of Activities.

Participants by arm

Arm	Count
Main Study: Ceralasertib + Durvalumab Participants received ceralasertib 240 milligrams (mg) orally twice daily (BD) for 7 consecutive days (Days 1 to 7), and on Day 8, participants received 1500 mg durvalumab as an intravenous (IV) infusion once in every 28 days. This 28-day cycle was repeated until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion was met.	100
Main Study: Ceralasertib Monotherapy Participants received ceralasertib monotherapy 240 mg orally BD from Days 1 to 7, once in every 28 days. This 28-day cycle was repeated until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion was met.	51
Biopsy Study: Ceralasertib + Durvalumab Participants received ceralasertib monotherapy 240 mg orally BD for 7 consecutive days (Days 1 to 7) on Cycle 0. Onwards Cycle 1, participants received ceralasertib 240 mg orally BD for 7 consecutive days (Days 1 to 7) plus durvalumab 1500 mg as IV infusion on Day 8 once in every 28 days. This 28-day cycle was repeated until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation criterion was met.	41
Total	192

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Database lock	2	0	0
Overall Study	Death	43	23	14
Overall Study	Disease progression	1	0	0
Overall Study	Lost to Follow-up	1	0	0
Overall Study	Other	0	0	9
Overall Study	Patient Is on Survival Follow Up Beyond DCO	1	0	0
Overall Study	Patients ongoing in the study at data cut-off (DCO) of 12-April-2024	19	3	6
Overall Study	Physician Decision	1	1	0
Overall Study	Progressive Disease	1	2	0
Overall Study	Study Terminated by Sponsor	22	14	7
Overall Study	Subject not treated	0	0	2
Overall Study	Withdrawal by Subject	9	8	5

Baseline characteristics

Characteristic	Main Study: Ceralasertib Monotherapy	Biopsy Study: Ceralasertib + Durvalumab	Total	Main Study: Ceralasertib + Durvalumab
Age, Continuous	62.9 Years STANDARD_DEVIATION 12.6	61.4 Years STANDARD_DEVIATION 11.9	62.6 Years STANDARD_DEVIATION 13	62.9 Years STANDARD_DEVIATION 13.6
Race/Ethnicity, Customized Asian	7 Participants	0 Participants	16 Participants	9 Participants
Race/Ethnicity, Customized Not reported	4 Participants	10 Participants	24 Participants	10 Participants
Race/Ethnicity, Customized Other	1 Participants	0 Participants	3 Participants	2 Participants
Race/Ethnicity, Customized White	39 Participants	31 Participants	149 Participants	79 Participants
Sex: Female, Male Female	22 Participants	16 Participants	80 Participants	42 Participants
Sex: Female, Male Male	29 Participants	25 Participants	112 Participants	58 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	43 / 100	23 / 51	14 / 41
other Total, other adverse events	86 / 97	43 / 52	34 / 41
serious Total, serious adverse events	19 / 97	5 / 52	9 / 41

Outcome results

Primary

Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Center Tumor Region

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.

Time frame: Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Population: Pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of study treatment with at least 1 reportable post-baseline pharmacodynamic measurement. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.

Arm	Measure	Group	Value (MEAN)	Dispersion
Main Study: Ceralasertib + Durvalumab	Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Center Tumor Region	On-treatment	-0.976 Percent change	Standard Deviation 2.92
Main Study: Ceralasertib + Durvalumab	Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Center Tumor Region	Off-treatment	-0.451 Percent change	Standard Deviation 1.357

Primary

Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Invasive Margin Region

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.

Time frame: Baseline, Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)

Population: The PD analysis set included all participants who received at least 1 dose of study treatment with at least 1 reportable post-baseline pharmacodynamic measurement. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.

Arm	Measure	Value (MEDIAN)
Main Study: Ceralasertib + Durvalumab	Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Invasive Margin Region	NA Percent change

Primary

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)

Arm	Measure	Group	Value (MEAN)	Dispersion
Main Study: Ceralasertib + Durvalumab	Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Center Tumor Region	On-treatment	-183.589 Change in cells per mm^2	Standard Deviation 740.398
Main Study: Ceralasertib + Durvalumab	Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Center Tumor Region	Off-treatment	-85.259 Change in cells per mm^2	Standard Deviation 396.091

Primary

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)

Arm	Measure	Value (MEDIAN)
Main Study: Ceralasertib + Durvalumab	Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Invasive Margin Region	NA Change in cells per mm^2

Primary

Main Study: Objective Response Rate (ORR)

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.

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)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment. Participants were summarized according to the actual treatment received.~Here, two participants, who were randomized to the Main Study: Ceralasertib + Durvalumab group, started with ceralasertib but did not receive durvalumab. Hence, they are summarized in the Main Study: Ceralasertib monotherapy group (actual treatment group) for the outputs presented in the safety analysis set.

Arm	Measure	Value (NUMBER)
Main Study: Ceralasertib + Durvalumab	Main Study: Objective Response Rate (ORR)	9.3 Percentage of participants
Main Study: Ceralasertib Monotherapy	Main Study: Objective Response Rate (ORR)	5.8 Percentage of participants

Secondary

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

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.

Time frame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)