| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable or Advanced Melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025655 |
| E.1.2 | Term | Malignant melanoma of skin |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10027156 |
| E.1.2 | Term | Skin melanomas (excl ocular) |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An open-label, non-randomised, biopsy sub-study is planned in patients suitable for 3 mandatory biopsies. Patients recruited into the biopsy sub-study will receive 1 cycle of ceralasertib monotherapy (Cycle 0) followed by ceralasertib plus durvalumab from Cycle 1.
Primary Objective:
●To assess changes in CD8+ T cell infiltration of tumours induced by ceralasertib monotherapy.
Secondary Objectives:
●To estimate the effectiveness of ceralasertib plus durvalumab by assessment of ORR, DoR, TTR, change in tumour size, PFS and OS.
●To collect tumour tissue samples, or utilise residual samples, for the analysis of tumoural biomarkers that change following treatment with ceralasertib.
●To assess changes in the proliferation of carcinoma and/or immune cells within tumours induced by ceralasertib monotherapy |
|
| E.3 | Principal inclusion criteria |
Main Study
4. Patient must have a histologically or cytologically confirmed diagnosis of unresectable or metastatic melanoma of cutaneous, acral or mucosal subtype.
5. Availability of an archival tumour sample and a fresh tumour biopsy taken at screening, if medically feasible as per investigator assessment. If a mandatory fresh biopsy is not feasible, the patient is permitted to enrol if they have an archival sample up to 5 years.
6. 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, eg, nivolumab, pembrolizumab, or atezolizumab, or the combination of nivolumab and ipilimumab. Confirmed progression is defined as radiologic progression confirmed by a second scan at 4 to 12 weeks after the initial scan showing disease progression or, a single scan showing radiological progression accompanied by correlative symptoms suggestive to disease progression. Patients who received adjuvant therapy for previously resected disease with PD-(L)1 agents may also be eligible if disease recurrence occurred while still receiving the anti-PD-(L)1 therapy or < 12 weeks from the last dose of the anti-PD-(L)1 therapy.
7. No intervening treatment eg, investigational therapy is permitted between the anti-PD-(L)1 therapy and study treatment (except targeted therapy is allowed).
9. BRAF V600E or V600K mutation status must be known at screening.
12. Measurable disease by RECIST 1.1. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements. Tumour assessment by CT scan or MRI must be performed within 28 days prior to randomisation. Cutaneous lesions and other superficial lesions are not considered measurable disease lesions, but may be considered as non-target lesions. For patients in the main study: if the patient has only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from the non-target lesion or archival tissue.
Other inclusion criteria per protocol apply
Biopsy Sub-Study
Patients are eligible to be included in the biopsy sub-study only if they meet all of the inclusion/ exclusion criteria of the main study and all of the following criteria:
1. Consent to the provision of 3 mandatory tumour biopsies.
2. 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.
3. Lesions used for biopsy should be different from those used as RECIST lesions, unless there are no other lesions suitable for biopsy.
4. Lesions used for biopsy may have received prior radiation therapy only if there is documented evidence of progression in the lesion after radiation treatment. |
|
| E.4 | Principal exclusion criteria |
Main Study
1. Patients must not have experienced a toxicity that led to permanent discontinuation of prior CPI treatment. Patients with unresolved ≥ Grade 2 toxicity from prior treatment (except alopecia and vitiligo) or ≥ Grade 1 for anti-PD-(L)1 antibody-related immune-mediated toxicities are excluded. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with durvalumab or ceralasertib may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead.
3. 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.
5. Uveal melanoma (eg, choroidal, iris, and ciliary body).
6. 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. Note: Patients with an endocrine AE of Grade ≤ 2 are permitted to enrol if they are stably maintained on appropriate replacement therapy and are asymptomatic.
10. 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.
12. Inadequate bone marrow and impaired hepatic or renal function as demonstrated by any of the following laboratory values:
●Haemoglobin <9.0 g/dL (no transfusions within the last 28 days).
●Absolute neutrophil count <1.5 x 109 /L.
●White blood cells ≤3 x 109 /L.
●Platelet count <100 x 109 /L.
●Albumin <33 g/L.
●Total bilirubin ≥ 1.5 × the ULN or ≥ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia).
●Aspartate aminotransferase/transaminase (SGOT)/Alanine aminotransferase/transaminase (ALT) (SGPT) ≥ 2.5 x institutional ULN unless liver metastases are present in which case it must be ≥ 5 x ULN.
●Serum creatinine > 1.5 x institutional ULN.
●Glomerular filtration rate < 45 mL/min, as assessed by Cockroft-Gault, MDRD or CKD-EPI formulae, EDTA clearance or 24-hour urine collection. The same method should be used throughout the study for each patient.
●Calculated creatinine clearance (CrCL) <45 mL/min as determined by Cockcroft-Gault (using actual body weight).
Males: CrCL (mL/min) = Weight (kg) × (140 - Age)/(72 × serum creatinine (mg/dL))
Females: CrCL (mL/min) = Weight (kg) × (140 - Age)/(72 × serum creatinine (mg/dL)) × 0.85
●International normalised ratio ≥ 1.5 or other evidence of impaired hepatic synthesis function. Patients on warfarin may participate in this study but it is recommended that their INR is monitored more frequently.
Other exclusion criteria per protocol apply
Biopsy Sub-Study
1. Patients must comply with the exclusion criteria described for the main study.
2. Patients with evidence of bleeding disease deemed unsafe for serial biopsies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Main Study:
●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.
Biopsy Sub-study:
●CD8+ T cells tumour infiltration assessed in baseline, on-treatment and off-treatment tumour biopsies. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main Study:
●Throughout the study.
Biopsy Sub-study:
●Baseline.
●On-treatment tumour biopsies.
●Off-treatment tumour biopsies. |
|
| E.5.2 | Secondary end point(s) |
Main Study:
●Median and landmark DoR estimates at 6, 9, 12, 15, and 18 months.
●Median TTR and proportion of patients with response at the first scheduled tumour assessment.
●Percentage change from baseline in TL tumour size at week 16 and best percentage change from baseline.
●Median and landmark PFS at 3, 6, 9, 12 months, and the hazard ratio comparing the 2 treatment arms.
●Median and landmark OS at 6, 9, 12, and 18 months, and the hazard ratio comparing the 2 treatment arms.
●Concentration of ceralasertib in plasma (peak and trough concentrations, as data allow; sparse sampling)
Biopsy Sub-study:
●As described for the main study, using the investigator assessment of tumour response per RECIST 1.1
●Pre-treatment presence and/or on-treatment and/or off-treatment changes in PD-L1 and pRAD50.
(including CD8+ T cells)
●Proliferation (using Ki67+ marker) of carcinoma and/or immune cells will be assessed in baseline, on-treatment and off-treatment tumour biopsies. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Main study:
●At 6, 9, 12, 15, 18 months.
●First scheduled tumour assessment.
●Week 16 from baseline.
●3, 6, 9, 12 months.
●At 6, 9, 12, 18 months.
●As data allow
Biopsy Sub-study:
●At 6, 9, 12, 15, 18 months. First scheduled tumour assessment. Week 16 from baseline. 3, 6, 9, 12 months. At 6, 9, 12, 18 months.
●Pre-Treatment. On-treatment. Off-treatment.
●At baseline, On-treatment and Off-treatment tumour biopsies. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last patient in the study or last scheduled procedure for the last patient in the study globally. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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