Clinical trial NCT05061134: A Study of Ceralasertib Monotherapy and Ceralasertib Plus Durvalumab in Patients With Melanoma and Resistance to PD-(L)1 Inhibition
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Melanoma
Keywords: Unresectable or Advanced Melanoma
Efficacy
Safety
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-09-29
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Main Study: Objective Response Rate (ORR)
timeFrame: 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)
measure: Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Center Tumor Region
timeFrame: Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-area in the Invasive Margin Region
timeFrame: Baseline, Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Center Tumor Region
timeFrame: Baseline, On-treatment (Cycle 0 Day 7), and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: Biopsy Study: Change From Baseline in CD8+ T-cells Tumour Infiltration-density in the Invasive Margin Region
timeFrame: Baseline, and Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Secondary outcomes:
measure: Main Study and Biopsy Study: Duration of Response (DOR)
timeFrame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
measure: Main Study and Biopsy Study: Time to Response
timeFrame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
measure: Main Study and Biopsy Study: Percentage Change From Baseline in Tumour Size
timeFrame: Main Study: at 16 weeks; Biopsy study: at 20 weeks
measure: Main Study and Biopsy Study: Progression Free Survival (PFS)
timeFrame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
measure: Main Study and Biopsy Study: Overall Survival (OS)
timeFrame: Cycle 1 Day 1 (each cycle is 28 days) until date of documented progression or data cut-off (2 years), whichever occurred first
measure: Main Study: Plasma Concentration of Ceralasertib
timeFrame: From Cycle 1 to Cycle 4: Day 7 and Day 8 of each cycle (each cycle is 28 days); 90 days follow-up
measure: Main Study and Biopsy Study: Number of Participants With Adverse Events (AEs)
timeFrame: 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
measure: Biopsy Study: Number of Participants With Presence of PD-L1 Overtime
timeFrame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: Biopsy Study: Number of Participants With Presence of pRAD50
timeFrame: On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: 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
timeFrame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: 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
timeFrame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: 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
timeFrame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
measure: 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
timeFrame: Baseline, On-treatment (Cycle 0 Day 7); Off-treatment (Cycle 0 Day 15-28) (each cycle is 28 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Tampa
country: United States
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state: Florida
city: Lutherville-Timonium
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state: Maryland
city: Nashville
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state: Tennessee
city: Darlinghurst
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city: East Melbourne
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city: Herston
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city: Woolloongabba
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city: Belgium
country: Belgium
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city: Bruges
country: Belgium
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city: Gent
country: Belgium
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city: Leuven
country: Belgium
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city: Edmonton
country: Canada
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state: Alberta
city: Toronto
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state: Ontario
city: Toronto
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state: Ontario
city: Ste-Foy
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state: Quebec
city: Bobigny
country: France
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city: Boulogne Billancourt
country: France
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city: Marseille Cedex 5
country: France
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city: Paris
country: France
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city: Pau Cedex
country: France
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city: Pierre-Benite
country: France
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city: Poitiers
country: France
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city: Vandoeuvre-Les-Nancy
country: France
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city: Villejuif Cedex
country: France
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city: Berlin
country: Germany
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city: Buxtehude
country: Germany
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city: Heidelberg
country: Germany
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city: Heilbronn
country: Germany
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city: Kiel
country: Germany
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city: Mainz
country: Germany
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city: München
country: Germany
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city: Regensburg
country: Germany
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city: Schwerin
country: Germany
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city: Tuebingen
country: Germany
facility: Research Site
city: Candiolo
country: Italy
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city: Milan
country: Italy
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city: Napoli
country: Italy
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city: Padova
country: Italy
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city: Perugia
country: Italy
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city: Roma
country: Italy
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city: Siena
country: Italy
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city: Goyang
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: Research Site
city: Brzozów
country: Poland
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city: Gdańsk
country: Poland
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city: Kraków
country: Poland
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city: Lodz
country: Poland
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city: Poznan
country: Poland
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city: Warszawa
country: Poland
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city: Barcelona
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
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city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Pamplona
country: Spain
facility: Research Site
city: Pozuelo de Alarcon
country: Spain
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Chelsea
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Northwood
country: United Kingdom
facility: Research Site
Study officials:
References: