A Randomised, Open-Label, Phase 2 Study of Ceralasertib Monotherapy and Ceralasertib plus Durvalumab in Patients with Unresectable or Advanced Melanoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Jun 2022 → ongoing

Decision date (initial)

2024-08-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512378-91-00

EudraCT number

2021-001722-21

ClinicalTrials.gov

NCT05061134

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To estimate the effectiveness of ceralasertib monotherapy and ceralasertib plus durvalumab by assessment of objective response rate (ORR) in patients with unresectable or advanced melanoma and primary
or secondary resistance to a PD-(L)1 inhibitor.
Biopsy Sub-Study: To assess changes in CD8+ T cell infiltration of tumours induced by ceralasertib monotherapy

Secondary objectives 4

1. To estimate the effectiveness of ceralasertib monotherapy and ceralasertib plus durvalumab by assessment of: ●Duration of Response (DoR) in patients with unresectable or advanced melanoma and primary or secondary resistance to a PD-(L)1 inhibitor. ●Time to objective response (TTR) in patients with unresectable or advanced melanoma and primary or secondary resistance to a PD-(L)1 inhibitor. ●Change in target lesion (TL) tumour size in patients with unresectable or advanced melanoma and primary or secondary resistance to a PD-(L)1 inhibitor. ●Progression free survival (PFS) in patients with unresectable or advanced melanoma and primary or secondary resistance to a PD-(L)1 inhibitor. ●Overall survival (OS) in patients with unresectable or advanced melanoma and primary or secondary resistance to a PD-(L)1 inhibitor. ●To assess the PK of ceralasertib alone and when in combination with durvalumab
2. Biopsy Sub-Study: To estimate the effectiveness of ceralasertib plus durvalumab by assessment of ORR, DoR, TTR, change in tumour size, PFS and OS
3. Biopsy Sub-Study: To collect tumour tissue samples, or utilise residual samples, for the analysis of tumoural biomarkers that change following treatment with ceralasertib
4. Biopsy Sub-Study: To assess changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy

Conditions and MedDRA coding

Unresectable or Advanced Melanoma

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment. When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. IPD Sharing Supporting Information Type: Study Protocol and Statistical Analysis Plan (SAP).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patient must have a histologically or cytologically confirmed diagnosis of unresectable or metastatic melanoma of cutaneous, acral or mucosal subtype
2. Availability of an archival tumour sample and a fresh tumour biopsy taken at screening.
3. Patient must have received at least 1 prior immunotherapy (anti-PD- (L)1 ± anti-CTLA-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.
4. No intervening treatment eg, investigational therapy is permitted between the anti-PD-(L)1 therapy and study treatment
5. BRAF V600E or V600K mutation status must be known at screening
6. Measurable disease by RECIST 1.1.
7. Biopsy Sub-Study: Consent to the provision of 3 mandatory tumour biopsies.
8. Biopsy Sub-Study: Have at least 1 tumour lesion medically accessible for 3 biopsies at baseline, on ceralasertib treatment and off ceralasertib treatment. Accessible lesions are defined as tumour lesions which are amenable to biopsy, unless clinically contraindicated or the patient has withdrawn consent. It is preferable that the same lesion is used for each biopsy, but if this is not possible, a patient may enrol if they have more than 1 lesion that is suitable for biopsy from the same tissue type eg, 3 cutaneous lesions
9. Biopsy Sub-Study: Lesions used for biopsy should be different from those used as RECIST lesions, unless there are no other lesions suitable for biopsy
10. Biopsy Sub-Study: Lesions used for biopsy may have received prior radiation therapy only if there is documented evidence of progression in the lesion after radiation treatment

Exclusion criteria 8

1. Patients must not have experienced a toxicity that led to permanent discontinuation of prior CPI treatment.
2. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment
3. Uveal melanoma
4. 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.
5. Active or prior documented autoimmune or inflammatory disorders (including, but not limited to inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, irritable bowel disease, Wegner syndrome, Hashimoto syndrome, hyperthyroidism, Sjogren's syndrome, glomerulonephritis, multiple sclerosis, vasculitis, heumatoid arthritis, idiopathic pulmonary fibrosis, pneumonitis, organising pneumonia, hepatitis, sarcoidosis, active tuberculosis) within the past 3 years
6. Inadequate bone marrow and impaired hepatic or renal function.
7. Biopsy Sub-Study: Patients must comply with the exclusion criteria described for the main study
8. Biopsy Sub-Study: Patients with evidence of bleeding disease deemed unsafe for serial biopsies

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary measure is the estimate of ORR for each experimental treatment arm, and a secondary measure of interest is the odds ratio of the ORR comparing the 2 treatment arms.
2. Biopsy Sub-study: CD8+ T cells tumour infiltration assessed in baseline, on-treatment and off-treatment tumour biopsies.

Secondary endpoints 9

1. Median and landmark DoR estimates at 6, 9, 12, 15, and 18 months
2. Median TTR and proportion of patients with response at the first scheduled tumour assessment
3. Percentage change from baseline in TL tumour size at week 16 and best percentage change from baseline
4. Median and landmark PFS at 3, 6, 9, 12 months, and the hazard ratio comparing the 2 treatment arms
5. Median and landmark OS at 6, 9, 12, and 18 months, and the hazard ratio comparing the 2 treatment arms
6. Concentration of ceralasertib in plasma (peak and trough concentrations, as data allow; sparse sampling)
7. Biopsy Sub-study: As described for the main study, using the investigator assessment of tumour response per RECIST 1.1
8. Biopsy Sub-study: Pre-treatment presence and/or on-treatment and/or off-treatment changes in PD-L1 and pRAD50
9. Biopsy Sub-study: Proliferation (using Ki67+ marker) of carcinoma and/or immune cells (including CD8+ T cells) will be assessed in baseline, on-treatment and off-treatment tumour biopsies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

6 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 54 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications