Detailed Description:
This study will consist of two treatment arms (Groups A and B).
Participants will be randomised in a 1:1 ratio to one of the two treatment groups:
- Group A: Ceralasertib plus durvalumab combination therapy Each 28-day cycle will begin
with ceralasertib administered orally followed by durvalumab administered intravenously.
- Group B: Docetaxel monotherapy Each 21-day cycle will begin with the administration of
docetaxel.
Inclusion Criteria:
- Histologically or cytologically documented NSCLC that is locally advanced or
metastatic according to Version 8 of the IASLC Staging Manual in Thoracic Oncology.
- Documented epidermal growth receptor factor (EGFR) and anaplastic lymphoma kinase
(ALK) wild-type status as determined at a local laboratory.
- Documented radiological PD whilst on or after receiving the most recent treatment
regimen.
- Eligible for second- or third-line therapy and must have received an anti-PD-(L)1
therapy and a platinum doublet containing therapy for locally advanced or metastatic
NSCLC either separately or in combination.
- Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance
status of 0 or 1.
- Adequate organ function and marrow reserve
- Minimum life expectancy of 12 weeks.
- Body weight > 30 kg and no cancer-associated cachexia.
- Negative pregnancy test (serum test) for women of childbearing potential (WOCBP).
Exclusion Criteria:
- Participant with mixed SCLC and NSCLC histology.
- History of another primary malignancy except for malignancy treated with curative
intent with no known active disease ≥ 5 years before the first dose of study
intervention.
- Persistent toxicities (CTCAE Grade > 2) caused by previous anticancer therapy.
- Active or prior documented autoimmune or inflammatory disorders.
- Participants who have received more than one line of prior anti-PD-(L)1, either alone
or in any combination.
- Participants:
1. Must not have experienced a toxicity that led to permanent discontinuation of the
prior anti-PD(L)1 therapy.
2. All AEs while receiving prior anti-PD(L)1 therapy must have completely resolved.
3. Must not have experienced a Grade ≥ 3 immune-mediated adverse event (imAE) or an
immune-related neurologic or ocular AE of any grade while receiving prior
anti-PD(L)1 therapy.
4. Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of > 10 mg
prednisone or equivalent per day.
- Participants who have received more than one prior line of platinum-based chemotherapy
in metastatic setting.
- Participants who have received a prior ataxia telangiectasia and Rad3-related protein
(ATR) inhibitor.
Primary outcome:
1. Overall Survival (OS) (Time Frame - Every 3 months (± 1 week) following objective progression of disease (PD) or treatment discontinuation (up to three years)):
The superiority of ceralasertib plus durvalumab combination therapy relative to docetaxel will be demonstrated by assessment of OS (HR with 95% CI and p-value) in participants with advanced NSCLC after second- or third-line therapy and without actionable genomic alterations. OS is defined as time from randomisation until the date of death due to any cause.
Secondary outcome:
1. Progression-Free Survival (PFS) (Time Frame - Up to 3 years):
PFS will be defined as the time from the date of randomisation until the date of objective PD.
2. Objective Response Rate (ORR) (Time Frame - Up to 3 years):
ORR is defined as the proportion of participant who have a Complete Response (CR) or Partial Response (PR) per RECIST 1.1.
3. Duration of Response (DoR) (Time Frame - Up to 3 years):
DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1.
4. Time To Response (TTR) (Time Frame - Up to 3 years):
TTR is defined as the time from randomisation until the date of first documented objective response.
5. Disease Control Rate (DCR) (Time Frame - At Week 18):
DCR at 18 weeks is defined as the percentage of participants who have a CR or PR or who have stable disease (SD) for at least 17 weeks.
6. Time to second progression or death (PFS2) (Time Frame - Up to 3 years):
Time from randomisation to PFS2 will be defined as the time from the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death.
7. Overall Survival (OS) at 12 months (Time Frame - At 12 months):
OS is defined as time from randomisation until the data of death due to any cause.
8. Time To Deterioration (TTD) of health-related quality of life (QoL) (Time Frame - Up to 3 years):
TTD is defined as the time from randomisation until the date of first confirmed deterioration.
9. TTD of physical function (Time Frame - Up to 3 years):
TTD in physical functioning is measured by the EORTC QLQ-C30 Physical Function subscale of the EORTC QLQ-C30.
10. Plasma concentrations for ceralasertib plus durvalumab combination therapy (Time Frame - Up to 3 years):
The PK plasma concentration of ceralasertib when administered in combination with durvalumab will be assessed.
11. Number of participants with Adverse Evens (AEs) (Time Frame - Up to 3 years):
The safety and tolerability of ceralasertib plus durvalumab combination therapy as compared with docetaxel will be assessed.
- Experimental: Group A: Ceralasertib plus durvalumab combination therapy
Participants will be administered ceralasertib orally followed by durvalumab administered intravenously. - Active Comparator: Group B: Docetaxel monotherapy
Participants will be administered docetaxel (standard of care) administered intravenously.
- Ceralasertib:
Participants will receive ceralasertib oral tablets. - Durvalumab:
Participants will receive durvalumab as an intravenous infusion. - Docetaxel:
Participants will received docetaxel as an intravenous infusion.
Quelle: ClinicalTrials.gov
