A Phase III, Randomized, Multicenter,Open-Label, Comparative Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination With Platinum-Based Chemotherapy for the First-Line Treatment in Patients With Extensive Disease Small-Cell Lung Cancer (SCLC) (CASPIAN)
Trial Snapshot
- Phase
- Phase 3
- Status
- Active, not recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 987
- Locations
- 208
- Primary Endpoint
- OS in the China Cohort; Assessed at China Cohort Second Analysis; D + EP Compared With EP and D + T + EP Compared With EP
Study Overview
Brief Summary
This is a phase III, randomized, open-label, multicenter, global study to determine the efficacy and safety of combining durvalumab ± tremelimumab with platinum based chemotherapy (EP) followed by durvalumab ± tremelimumab maintenance therapy versus EP alone as first-line treatment in patients with extensive-stage small-cell lung cancer
Detailed Description
Primary objective of this study is to assess the efficacy of durvalumab + tremelimumab + EP treatment compared with EP and the efficacy of durvalumab + EP treatment compared with EP in terms of OS.
All patients will be randomized in a 1:1:1 ratio in a stratified manner according to the planned platinum-based therapy for Cycle 1 (cisplatin or carboplatin) to receive treatment with durvalumab + tremelimumab + EP (Arm 1), durvalumab + EP (Arm 2), or standard of care- EP (Arm 3). Arm 1 and Arm 2 patients receive the treatment until confirmed disease progression while Arm 3 patients receive up to 6 cycles of EP and prophylactic cranial irradiation if clinically indicated, at the Investigators' discretion.Patients who have discontinued treatment due to toxicity or symptomatic deterioration, clinical progression, or who have commenced subsequent anticancer therapy will be followed up until confirmed disease progression and for survival.
Targeted population are adult patients (aged ≥18 years) with histologically or cytologically documented extensive disease (American Joint Committee on Cancer Stage (7th edition) IV SCLC [T any, N any,M1 a/b]), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan. Patients must have WHO/ECOG performance status of 0 or 1.
Tumor assessments will be performed at Screening as baseline with follow-up at Week 6 ±1 week from the date of randomization, at Week 12 ±1 week from the date of randomization, and then every 8 weeks ±1 week until confirmed objective disease progression.
An independent data monitoring committee (IDMC) comprised of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule of durvalumab ± tremelimumab in combination with platinum based chemotherapy at two early stages of enrolment.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 130 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically or cytologically documented extensive disease. Brain metastases; must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment.
- •Suitable to receive a platinum-based chemotherapy regimen as 1st line treatment.
- •Life expectancy ≥12 weeks at Day
- •ECOG 0 or 1 at enrolment.
- •No prior exposure to immune-mediated therapy excluding therapeutic anticancer vaccines.
Exclusion Criteria
- •Any history of radiotherapy to the chest prior to systemic therapy or planned consolidation chest radiation therapy (except paliative care outside of the chest).
- •Paraneoplastic syndrome of autoimmune nature, requiring systemic treatment or clinical symptomatology suggesting worsening of PNS
- •Active infection including tuberculosis, HIV, hepatitis B anc C
- •Active or prior documented autoimmune or inflammatory disorders
- •Uncontrolled intercurrent illness, including but not limited to interstitial lung disease.
Arms & Interventions
Arm 1
durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Durvalumab (Drug)
Arm 1
durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Carboplatin (Drug)
Arm 1
durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Cisplatin (Drug)
Arm 3
EP (carboplatin or cisplatin + etoposide)
Intervention: Cisplatin (Drug)
Arm 1
durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Etoposide (Drug)
Arm 1
durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Tremelimumab (Drug)
Arm 2
durvalumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Durvalumab (Drug)
Arm 2
durvalumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Carboplatin (Drug)
Arm 2
durvalumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Etoposide (Drug)
Arm 2
durvalumab+EP (carboplatin or cisplatin + etoposide)
Intervention: Cisplatin (Drug)
Arm 3
EP (carboplatin or cisplatin + etoposide)
Intervention: Etoposide (Drug)
Arm 3
EP (carboplatin or cisplatin + etoposide)
Intervention: Carboplatin (Drug)
Outcomes
Primary Outcomes
OS in the China Cohort; Assessed at China Cohort Second Analysis; D + EP Compared With EP and D + T + EP Compared With EP
Time Frame: From baseline until death due to any cause. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + T + EP vs EP in the China cohort was pre-specified at approximately 80% maturity (to ensure a similar maturity to the final analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP and D + T + EP vs EP at the time of the China cohort second analysis DCO (02 November 2020), and is comparable in terms of maturity with the final analysis of OS for D + EP vs EP and D + T + EP vs EP in the Global cohort. Analysis of D + EP vs EP at the China cohort first analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (China cohort second analysis) is presented as a secondary outcome measure.
Overall Survival (OS) in the Global Cohort; Assessed at Global Cohort Interim Analysis; D + EP Compared With EP
Time Frame: From baseline until death due to any cause. Assessed until global cohort interim analysis DCO (maximum of approximately 23 months).
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An interim analysis of OS in the global cohort was pre-specified after approximately 318 OS events occurred each between the D + EP and EP groups (60% maturity), and between the D + T + EP and EP groups (60% maturity). At the global cohort interim analysis DCO (11 March 2019), comparison of OS in the D + EP versus (vs) EP groups had crossed the pre-specified boundary. Since these results were considered final in terms of formal statistical testing, they are presented here as a primary outcome measure. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the global cohort final analysis is presented separately in the subsequent primary outcome measure.
OS in the China Cohort; Assessed at China Cohort First Analysis; D + EP Compared With EP
Time Frame: From baseline until death due to any cause. Assessed until China cohort first analysis DCO (maximum of approximately 19 months).
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + EP vs EP in the China cohort was pre-specified at approximately 60% maturity (to ensure a similar maturity to the interim analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP at the China cohort first analysis DCO (06 January 2020), and is comparable in terms of maturity with the interim analysis of OS for D + EP vs EP in the Global cohort. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the China cohort second analysis is presented separately in the subsequent primary outcome measure.
OS in the Global Cohort; Assessed at Global Cohort Final Analysis; D + EP Compared With EP and D + T + EP Compared With EP
Time Frame: From baseline until death due to any cause. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This primary outcome measure presents OS for the analysis of D + EP vs EP and D + T + EP vs EP at the time of the global cohort final analysis DCO (27 January 2020). Analysis of D + EP vs EP at the global cohort interim analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (global cohort final analysis) is presented as a secondary outcome measure.
Secondary Outcomes
- Percentage of Patients Alive and Progression Free at 12 Months (APF12) in the Global Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 12 months post-randomization.)
- PK of Tremelimumab; Peak and Trough Serum Concentrations in the Global Cohort(Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the global cohort final analysis DCO (27 January 2020).)
- Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) in the Global Cohort(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until global cohort final analysis DCO (maximum of approximately 33 months).)
- OS in the Global Cohort; D + T + EP Compared With D + EP(From baseline until death due to any cause. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).)
- Progression-Free Survival (PFS) in the Global Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).)
- Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab in the Global Cohort(Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, durvalumab). Assessed at the global cohort final analysis DCO (27 January 2020).)
- Change From Baseline in Primary PRO Symptoms as Assessed by EORTC QLQ in the Global Cohort; D + T + EP Compared With EP(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.)
- Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations in the Global Cohort(Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the global cohort final analysis DCO (27 January 2020).)
- Number of Patients With ADA Response to Tremelimumab in the Global Cohort(Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, tremelimumab). Assessed at the global cohort final analysis DCO (27 January 2020).)
- Time to Deterioration of Health-Related Quality of Life (HRQoL) and Patient Reported Outcome (PRO) Symptoms, Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) in the Global Cohort(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until global cohort final analysis DCO (maximum of approximately 33 months).)
- OS in the China Cohort; D + T + EP Compared With D + EP(From baseline until death due to any cause. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).)
- Objective Response Rate (ORR) in the Global Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).)
- Percentage of Patients Alive and Progression Free at 6 Months (APF6) in the Global Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 6 months post-randomization.)
- Percentage of Patients Alive at 18 Months (OS18) in the Global Cohort(At 18 months post-randomization. Assessed at the global cohort final analysis DCO (27 January 2020).)
- Change From Baseline in Primary Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the Global Cohort; D + EP Compared With EP(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.)
- APF12 in the China Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 12 months post-randomization.)
- OS18 in the China Cohort(At 18 months post-randomization. Assessed at the China cohort second analysis DCO (02 November 2020).)
- Time to Deterioration of HRQoL and PRO Symptoms, Assessed Using EORTC QLQ in the China Cohort(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until China cohort second analysis DCO (maximum of approximately 29 months).)
- Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-LC13 in the China Cohort(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until China cohort second analysis DCO (maximum of approximately 29 months).)
- Change From Baseline in Primary PRO Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the China Cohort; D + T + EP Compared With EP(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.)
- PFS in the China Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).)
- PK of Durvalumab; Peak and Trough Serum Concentrations in the China Cohort(Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the China cohort second analysis DCO (02 November 2020).)
- Number of Patients With ADA Response to Tremelimumab in the China Cohort(Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, tremelimumab). Assessed at the China cohort second analysis DCO (02 November 2020).)
- ORR in the China Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).)
- APF6 in the China Cohort(Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 6 months post-randomization.)
- PK of Tremelimumab; Peak and Trough Serum Concentrations in the China Cohort(Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the China cohort second analysis DCO (02 November 2020).)
- Number of Patients With ADA Response to Durvalumab in the China Cohort(Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, durvalumab). Assessed at the China cohort second analysis DCO (02 November 2020).)
- Change From Baseline in Primary Symptoms as Assessed by EORTC QLQ in the China Cohort; D + EP Compared With EP(At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.)