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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Ceralasertib
* Biological: Durvalumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main study: Ceralasertib + Durvalumab<br>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<br>* Ceralasertib (240 mg) will be administered orally twice daily.<br>Biological: Durvalumab<br>* 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.<br>|
| Experimental: Main study: Ceralasertib<br>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<br>* Ceralasertib (240 mg) will be administered orally twice daily.<br>|
| Experimental: Biopsy Sub-study: Ceralasertib + Durvalumab<br>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<br>* Ceralasertib (240 mg) will be administered orally twice daily.<br>Biological: Durvalumab<br>* 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.<br>|
| Experimental: Biopsy study: Ceralasertib<br>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<br>* Ceralasertib (240 mg) will be administered orally twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main study: Objective response rate (ORR) | ORR is the proportion of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumours (RECIST 1.1). 1 cycle length is 28 days. | 8 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years) | 
| Biopsy sub-study: CD8+ T-cells tumour infiltration assessed in baseline, on-treatment and off-treatment tumour biopsies | Changes in CD8+ T cell infiltration of tumours induced by ceralasertib monotherapy will be evaluated. 1 cycle length is 28 days. | Screening, on-treatment and off-treatment during Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main study and Biopsy sub-study: Duration of Response (DoR) | DoR will be defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 as assessed by BICR or death due to any cause. 1 cycle length is 28 days. | Main study: 8 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years); Biopsy study: 12 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years) | 
| Main study and Biopsy sub-study: Time to objective response (TTR) | Time to response is defined as the time from randomisation (or date of first dose of study treatment, for the biopsy sub-study) until the date of first documented objective response, which is subsequently confirmed per RECIST 1.1 as assessed by BICR. 1 cycle length is 28 days. | Main study: 8 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years); Biopsy study: 12 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years) | 
| Main study and Biopsy sub-study: Percentage change in target lesion tumour size | Percentage change from baseline in tumor lesions tumour size, where tumor size is the sum of the longest diameters of the target lesions. 1 cycle length is 28 days. | Main study: 16 weeks; Biopsy study: 20 weeks | 
| Biopsy sub-study: ORR | ORR is defined as the proportion of participants who have a confirmed CR or PR, as determined by BICR per RECIST 1.1. 1 cycle length is 28 days. | Biopsy study: 12 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years) | 
| Main study and Biopsy sub-study: Progression free survival (PFS) | PFS is defined as time from randomisation (or date of first dose for the biopsy sub-study) until progression per RECIST 1.1 as assessed by BICR or death due to any cause. | From screening until objective disease progression or death (approx. up to 1 year) | 
| Main study and Biopsy sub-study: Overall survival (OS) | OS is defined as time from randomisation (or date of first dose for the biopsy sub-study) until the date of death due to any cause | From screening until death (approx. up to 2 years) | 
| Biopsy sub-study: Pre-treatment presence and/or on-treatment and/or off-treatment changes in PD-L1 and pRAD50 | Tumour tissue samples for the analysis of tumoural biomarkers that change following treatment with ceralasertib will collected. 1 cycle length is 28 days. | Biopsy study: Screening, on-treatment and off-treatment during Cycle 1 | 
| Main study and Biopsy sub-study: Number of adverse events and serious adverse events | Adverse events will recorded to evalute the safety and tolerability of the study drugs. | From screening until treatment discontinuation plus 90 day safety follow up (approx. up to 1 year) | 
| Main study: Concentration of ceralasertib in plasma | To assess the Pharmakokinetic (plasma peak and trough concentrations) of ceralasertib alone and when in combination with durvalumab. | Cycle 1, 2, 3 Day 7 (each cycle is 28 days) | 
| Biopsy sub-study: Assessment of proliferation of carcinoma in Ki67 marker (Marker Of Proliferation Ki-67) or CD8+ T cells immune cells | To assess changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy. | From baseline, on-treatment and off-treatment until 24 months after the last patient (approx 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unresectable or Advanced Melanoma, Efficacy, Safety