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

Melanoma Clinical Trial

— MONETTE  

Official 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05061134
• Other study ID #: D533AC00001
• Secondary ID: 2021-001722-21
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 11, 2022
• Est. completion date: April 12, 2024

Study information

• Verified date: January 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 194
• Est. completion date: April 12, 2024
• Est. primary completion date: April 12, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma

Intervention

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.

Locations

Country	Name	City	State
Australia	Research Site	East Melbourne
Australia	Research Site	Herston
Australia	Research Site	Woolloongabba
Belgium	Research Site	Belgium
Belgium	Research Site	Gent
Belgium	Research Site	Leuven
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	London	Ontario
Canada	Research Site	Ste-Foy	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
France	Research Site	Bobigny
France	Research Site	Boulogne Billancourt
France	Research Site	Marseille Cedex 5
France	Research Site	Paris
France	Research Site	Pau Cedex
France	Research Site	Pierre Benite Cedex
France	Research Site	Poitiers
France	Research Site	Vandoeuvre-Les-Nancy
France	Research Site	Villejuif Cedex
Germany	Research Site	Berlin
Germany	Research Site	Buxtehude
Germany	Research Site	Heidelberg
Germany	Research Site	Heilbronn
Germany	Research Site	Kiel
Germany	Research Site	Mainz
Germany	Research Site	München
Germany	Research Site	Regensburg
Germany	Research Site	Schwerin
Germany	Research Site	Tuebingen
Italy	Research Site	Candiolo
Italy	Research Site	Milan
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Perugia
Italy	Research Site	Roma
Italy	Research Site	Siena
Korea, Republic of	Research Site	Goyang
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Poland	Research Site	Brzozów
Poland	Research Site	Gdansk
Poland	Research Site	Kraków
Poland	Research Site	Lodz
Poland	Research Site	Poznan
Poland	Research Site	Warszawa
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Málaga
Spain	Research Site	Pozuelo de Alarcon
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Chelsea
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Northwood
United States	Research Site	Los Angeles	California
United States	Research Site	Lutherville-Timonium	Maryland
United States	Research Site	Nashville	Tennessee
United States	Research Site	Sacramento	California
United States	Research Site	San Francisco	California
United States	Research Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)