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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT05061134
• Collaborator: (none)
• Enrollment: 195
• Locations: 75
• Arms: 4
• Anticipated Duration (Months): 20.7
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Ceralasertib; Biological: Durvalumab	Phase 2

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 195 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Aug 11, 2022
• Anticipated Primary Completion Date: May 3, 2024
• Anticipated Study Completion Date: May 3, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Main study: Ceralasertib + Durvalumab 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; 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.
Experimental: Main study: Ceralasertib 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; Ceralasertib (240 mg) will be administered orally twice daily.
Experimental: Biopsy Sub-study: Ceralasertib + Durvalumab 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; 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.
Experimental: Biopsy study: Ceralasertib 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; Ceralasertib (240 mg) will be administered orally twice daily.

Outcome Measures

Primary Outcome Measures

1. Main study: Objective response rate (ORR) [8 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years)]

   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.

2. Biopsy sub-study: CD8+ T-cells tumour infiltration assessed in baseline, on-treatment and off-treatment tumour biopsies [Screening, on-treatment and off-treatment during Cycle 1]

   Changes in CD8+ T cell infiltration of tumours induced by ceralasertib monotherapy will be evaluated. 1 cycle length is 28 days.

Secondary Outcome Measures

1. Main study and Biopsy sub-study: Duration of Response (DoR) [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)]

   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.

2. Main study and Biopsy sub-study: Time to objective response (TTR) [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)]

   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.

3. Main study and Biopsy sub-study: Percentage change in target lesion tumour size [Main study: 16 weeks; Biopsy study: 20 weeks]

   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.

4. Biopsy sub-study: ORR [Biopsy study: 12 weeks after the start of treatment (Cycle 1 Day 1) until objective disease progression (approx 2 years)]

   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.

5. Main study and Biopsy sub-study: Progression free survival (PFS) [From screening until objective disease progression or death (approx. up to 1 year)]

   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.

6. Main study and Biopsy sub-study: Overall survival (OS) [From screening until death (approx. up to 2 years)]

   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

7. Biopsy sub-study: Pre-treatment presence and/or on-treatment and/or off-treatment changes in PD-L1 and pRAD50 [Biopsy study: Screening, on-treatment and off-treatment during Cycle 1]

   Tumour tissue samples for the analysis of tumoural biomarkers that change following treatment with ceralasertib will collected. 1 cycle length is 28 days.

8. Main study and Biopsy sub-study: Number of adverse events and serious adverse events [From screening until treatment discontinuation plus 90 day safety follow up (approx. up to 1 year)]

   Adverse events will recorded to evalute the safety and tolerability of the study drugs.

9. Main study: Concentration of ceralasertib in plasma [Cycle 1, 2, 3 Day 7 (each cycle is 28 days)]

   To assess the Pharmakokinetic (plasma peak and trough concentrations) of ceralasertib alone and when in combination with durvalumab.

10. Biopsy sub-study: Assessment of proliferation of carcinoma in Ki67 marker (Marker Of Proliferation Ki-67) or CD8+ T cells immune cells [From baseline, on-treatment and off-treatment until 24 months after the last patient (approx 2 years)]

    To assess changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States	90024
2	Research Site	Sacramento	California	United States	95816
3	Research Site	San Francisco	California	United States	94143
4	Research Site	Tampa	Florida	United States	33612
5	Research Site	Lutherville-Timonium	Maryland	United States	21093
6	Research Site	Rochester	Minnesota	United States	55905-0001
7	Research Site	New York	New York	United States	10065
8	Research Site	Pittsburgh	Pennsylvania	United States	15232
9	Research Site	Nashville	Tennessee	United States	37232
10	Research Site	East Melbourne		Australia	3002
11	Research Site	Herston		Australia	4029
12	Research Site	Woolloongabba		Australia	4102
13	Research Site	Belgium		Belgium	1200
14	Research Site	Bruges		Belgium	8000
15	Research Site	Gent		Belgium	9000
16	Research Site	Leuven		Belgium	3000
17	Research Site	Edmonton	Alberta	Canada	t6G1Z2
18	Research Site	London	Ontario	Canada	N6A 4G5
19	Research Site	Toronto	Ontario	Canada	M4N 3M5
20	Research Site	Toronto	Ontario	Canada	M5G 2M9
21	Research Site	Ste-Foy	Quebec	Canada	G1V 4G2
22	Research Site	Bobigny		France	93009
23	Research Site	Boulogne Billancourt		France	92100
24	Research Site	Marseille Cedex 5		France	13385
25	Research Site	Paris		France	75475
26	Research Site	Pau Cedex		France	64046
27	Research Site	Pierre Benite Cedex		France	69310
28	Research Site	Poitiers		France	86021
29	Research Site	Rennes		France	35042
30	Research Site	Vandoeuvre-Les-Nancy		France	54511
31	Research Site	Villejuif Cedex		France	94805
32	Research Site	Berlin		Germany	10117
33	Research Site	Berlin		Germany	12351
34	Research Site	Buxtehude		Germany	21614
35	Research Site	Dresden		Germany	01307
36	Research Site	Heidelberg		Germany	69120
37	Research Site	Heilbronn		Germany	74078
38	Research Site	Kiel		Germany	24105
39	Research Site	Köln		Germany	50924
40	Research Site	Mainz		Germany	55131
41	Research Site	München		Germany	80337
42	Research Site	Regensburg		Germany	93053
43	Research Site	Schwerin		Germany	19049
44	Research Site	Tuebingen		Germany	D-72076
45	Research Site	Aviano		Italy	33081
46	Research Site	Candiolo		Italy	10060
47	Research Site	Milano		Italy	20141
48	Research Site	Napoli		Italy	80131
49	Research Site	Padova		Italy	35128
50	Research Site	Perugia		Italy	06156
51	Research Site	Roma		Italy	00168
52	Research Site	Siena		Italy	53100
53	Research Site	Goyang		Korea, Republic of	410-769
54	Research Site	Seoul		Korea, Republic of	03722
55	Research Site	Seoul		Korea, Republic of	05505
56	Research Site	Seoul		Korea, Republic of	06351
57	Research Site	Brzozów		Poland	36-200
58	Research Site	Gdańsk		Poland	80-214
59	Research Site	Kraków		Poland	31-115
60	Research Site	Lodz		Poland	93-513
61	Research Site	Poznan		Poland	60-355
62	Research Site	Warszawa		Poland	02-781
63	Research Site	Barcelona		Spain	08035
64	Research Site	Barcelona		Spain	08041
65	Research Site	Madrid		Spain	28007
66	Research Site	Madrid		Spain	28027
67	Research Site	Madrid		Spain	28034
68	Research Site	Madrid		Spain	28040
69	Research Site	Málaga		Spain	29009
70	Research Site	Pozuelo de Alarcon		Spain	28223
71	Research Site	Cambridge		United Kingdom	CB2 0QQ
72	Research Site	Chelsea		United Kingdom	SW3 6JJ
73	Research Site	Manchester		United Kingdom	M20 4BX
74	Research Site	Northwood		United Kingdom	HA6 2RN
75	Research Site	Southampton		United Kingdom	SO166YD

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT05061134
• Other Study ID Numbers: D533AC00001; 2021-001722-21
• First Posted: Sep 29, 2021
• Last Update Posted: Aug 25, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by AstraZeneca: Unresectable or Advanced Melanoma; Efficacy; Safety
• Additional relevant MeSH terms: Melanoma; Durvalumab

Study Results

No Results Posted as of Aug 25, 2022