Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer (CASPIAN) (CASPIAN)

• ClinicalTrials.gov Identifier: NCT03043872
• Recruitment Status: Active, not recruiting
• First Posted: February 6, 2017
• Results First Posted: March 4, 2021
• Last Update Posted: September 28, 2022
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

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

Condition or disease	Intervention/treatment	Phase
Small Cell Lung Carcinoma Extensive Disease	Drug: Durvalumab; Drug: Tremelimumab; Drug: Carboplatin; Drug: Cisplatin; Drug: Etoposide	Phase 3

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 (Clinical Trial)
• Actual Enrollment: 987 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: March 27, 2017
• Actual Primary Completion Date: January 27, 2020
• Estimated Study Completion Date: December 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1; durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)	Drug: Durvalumab; IV infusions every 3 weeks for 12 weeks (4 cycles) and every 4 weeks thereafter until PD or other discontinuation criteria.; Drug: Tremelimumab; IV infusions every 3 weeks for 12 weeks(4 cycles). An additional dose of tremelimumab will be administered in the week 16.; Drug: Carboplatin; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3; Drug: Cisplatin; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3; Drug: Etoposide; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3
Experimental: Arm 2; durvalumab+EP (carboplatin or cisplatin + etoposide)	Drug: Durvalumab; IV infusions every 3 weeks for 12 weeks (4 cycles) and every 4 weeks thereafter until PD or other discontinuation criteria.; Drug: Carboplatin; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3; Drug: Cisplatin; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3; Drug: Etoposide; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3
Active Comparator: Arm 3; EP (carboplatin or cisplatin + etoposide)	Drug: Carboplatin; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3; Drug: Cisplatin; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3; Drug: Etoposide; up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.

Secondary Outcome Measures :

1. OS in the Global Cohort; D + T + EP Compared With D + 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 the 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 secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP in the global cohort. The alternative treatment comparisons in the global cohort were performed as primary outcome measures.
2. Progression-Free Survival (PFS) in the Global Cohort [ Time Frame: 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). ]
   PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir) and an absolute increase of ≥5 millimeters (mm) for the sum from nadir. For evaluation of non-target lesions (NTLs), PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.
3. Objective Response Rate (ORR) in the Global Cohort [ Time Frame: 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). ]
   ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR). CR was defined as disappearance of all TLs since baseline (any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size [<10 mm short axis]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).
4. Percentage of Patients Alive and Progression Free at 6 Months (APF6) in the Global Cohort [ Time Frame: 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. ]
   The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.
5. Percentage of Patients Alive and Progression Free at 12 Months (APF12) in the Global Cohort [ Time Frame: 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. ]
   The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.
6. Percentage of Patients Alive at 18 Months (OS18) in the Global Cohort [ Time Frame: At 18 months post-randomization. Assessed at the global cohort final analysis DCO (27 January 2020). ]
   OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.
7. Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations in the Global Cohort [ Time Frame: 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). ]
   To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
8. PK of Tremelimumab; Peak and Trough Serum Concentrations in the Global Cohort [ Time Frame: 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). ]
   To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
9. Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab in the Global Cohort [ Time Frame: 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). ]
   Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of neutralizing antibody (nAb) was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.
10. Number of Patients With ADA Response to Tremelimumab in the Global Cohort [ Time Frame: 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). ]
    Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.
11. 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 [ Time Frame: 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). ]
    The EORTC QLQ-Core 30 version 3 (QLQ-C30 v3) was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
12. Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) in the Global Cohort [ Time Frame: 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). ]
    The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
13. Change From Baseline in Primary PRO Symptoms as Assessed by EORTC QLQ in the Global Cohort; D + T + EP Compared With EP [ Time Frame: 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. ]
    A mixed model repeated measures (MMRM) analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs P. Analysis of D + EP vs EP is presented in a separate outcome measure.
14. Change From Baseline in Primary Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the Global Cohort; D + EP Compared With EP [ Time Frame: 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. ]
    A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.
15. OS in the China Cohort; D + T + EP Compared With D + 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 the 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 secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP at the China cohort second analysis DCO (02 November 2020). The alternative treatment comparisons were performed as primary outcome measures.
16. PFS in the China Cohort [ Time Frame: 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). ]
    PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, PD) was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) and an absolute increase of ≥5 mm for the sum from nadir. For evaluation of NTLs, PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.
17. ORR in the China Cohort [ Time Frame: 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). ]
    ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of CR or PR. CR was defined as disappearance of all TLs since baseline (any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size [<10 mm short axis]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).
18. APF6 in the China Cohort [ Time Frame: 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. ]
    The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.
19. APF12 in the China Cohort [ Time Frame: 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. ]
    The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.
20. OS18 in the China Cohort [ Time Frame: At 18 months post-randomization. Assessed at the China cohort second analysis DCO (02 November 2020). ]
    OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.
21. PK of Durvalumab; Peak and Trough Serum Concentrations in the China Cohort [ Time Frame: 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). ]
    To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
22. PK of Tremelimumab; Peak and Trough Serum Concentrations in the China Cohort [ Time Frame: 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). ]
    To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
23. Number of Patients With ADA Response to Durvalumab in the China Cohort [ Time Frame: 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). ]
    Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.
24. Number of Patients With ADA Response to Tremelimumab in the China Cohort [ Time Frame: 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). ]
    Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.
25. Time to Deterioration of HRQoL and PRO Symptoms, Assessed Using EORTC QLQ in the China Cohort [ Time Frame: 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). ]
    The EORTC QLQ-C30 v3 was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
26. Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-LC13 in the China Cohort [ Time Frame: 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). ]
    The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
27. 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 [ Time Frame: 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. ]
    A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs EP. Analysis of D + EP vs EP is presented in a separate outcome measure.
28. Change From Baseline in Primary Symptoms as Assessed by EORTC QLQ in the China Cohort; D + EP Compared With EP [ Time Frame: 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. ]
    A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as >75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 130 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. 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.
2. Suitable to receive a platinum-based chemotherapy regimen as 1st line treatment.
3. Life expectancy ≥12 weeks at Day 1.
4. ECOG 0 or 1 at enrolment.
5. No prior exposure to immune-mediated therapy excluding therapeutic anticancer vaccines.

Exclusion criteria:

1. Any history of radiotherapy to the chest prior to systemic therapy or planned consolidation chest radiation therapy (except paliative care outside of the chest).
2. Paraneoplastic syndrome of autoimmune nature, requiring systemic treatment or clinical symptomatology suggesting worsening of PNS
3. Active infection including tuberculosis, HIV, hepatitis B anc C
4. Active or prior documented autoimmune or inflammatory disorders
5. Uncontrolled intercurrent illness, including but not limited to interstitial lung disease.

Contacts and Locations

Locations

United States, Alabama

Research Site

Birmingham, Alabama, United States, 35235

United States, Arizona

Research Site

Scottsdale, Arizona, United States, 85259

United States, Arkansas

Research Site

Rogers, Arkansas, United States, 72758

United States, California

Research Site

Santa Monica, California, United States, 90404

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06520

United States, Georgia

Research Site

Athens, Georgia, United States, 30607

United States, Indiana

Research Site

Fort Wayne, Indiana, United States, 46804

Research Site

Muncie, Indiana, United States, 47303

United States, Kansas

Research Site

Leawood, Kansas, United States, 66209

Research Site

Wichita, Kansas, United States, 67214

United States, Kentucky

Research Site

Paducah, Kentucky, United States, 42003

United States, Michigan

Research Site

Grand Rapids, Michigan, United States, 49503

United States, New York

Research Site

Mineola, New York, United States, 11501

United States, Ohio

Research Site

Cleveland, Ohio, United States, 44106

Research Site

Columbus, Ohio, United States, 43219

United States, Pennsylvania

Research Site

Harrisburg, Pennsylvania, United States, 17109

United States, South Dakota

Research Site

Sioux Falls, South Dakota, United States, 57104

United States, Tennessee

Research Site

Nashville, Tennessee, United States, 37203

United States, Washington

Research Site

Kennewick, Washington, United States, 99336

Argentina

Research Site

Buenos Aires, Argentina, C1118AAT

Research Site

Ciudad de Buenos Aires, Argentina, C1426

Research Site

Mar del Plata, Argentina, 7600

Research Site

Rosario, Argentina, 2000

Research Site

San Miguel de Tucuman, Argentina, T4000IAK

Austria

Research Site

Linz, Austria, 4021

Research Site

Salzburg, Austria, 5020

Research Site

Wien, Austria, 1140

Research Site

Wien, Austria, 1210

Brazil

Research Site

Barretos, Brazil, 14784-400

Research Site

Curitiba, Brazil, 81520-060

Research Site

Passo Fundo, Brazil, 99010 260

Research Site

Porto Alegre, Brazil, 91350-200

Research Site

Ribeirão Preto, Brazil, 14048-900

Research Site

Rio de Janeiro, Brazil, 22793-080

Research Site

Salvador, Brazil, 41.950-610

Research Site

Santo André, Brazil, 09060-650

Research Site

São José do Rio Preto, Brazil, 15090-000

Research Site

São Paulo, Brazil, 03102-002

Bulgaria

Research Site

Panagyurishte, Bulgaria, 4500

Research Site

Plovdiv, Bulgaria, 4000

Research Site

Plovdiv, Bulgaria, 4004

Research Site

Sofia, Bulgaria, 1330

Research Site

Sofia, Bulgaria, 1431

Research Site

Sofia, Bulgaria, 1618

Research Site

Sofia, Bulgaria, 1784

Research Site

Varna, Bulgaria, 9010

China

Research Site

Beijing, China, 100142

Research Site

Beijing, China, 100730

Research Site

Beijing, China, 100853

Research Site

Bengbu, China, 233060

Research Site

Changchun, China, 130021

Research Site

Changsha, China, 410013

Research Site

Chengdu, China, 610041

Research Site

ChongQing, China, 400038

Research Site

Hangzhou, China, 310003

Research Site

Hangzhou, China, 310006

Research Site

Hangzhou, China, 310009

Research Site

Hefei, China, 230601

Research Site

Nanchang, China, 330006

Research Site

Nanjing, China, 210009

Research Site

Nanjing, China, 210029

Research Site

Shanghai, China, 200032

Research Site

Shanghai, China, 200433

Research Site

Shenyang, China, 110042

Research Site

Wenzhou, China, 325000

Research Site

Wuhan, China, 430022

Research Site

Wuhan, China, 430030

Research Site

Xi'an, China, 710038

Research Site

Xi'an, China, 710061

Research Site

Zhanjiang, China, 524001

Research Site

Zhengzhou, China, 450008

Research Site

Zhuhai, China, 519099

Research Site

Ürümqi, China, 830000

Czechia

Research Site

Brno, Czechia, 639 00

Research Site

Olomouc, Czechia, 775 21

Research Site

Ostrava - Vitkovice, Czechia, 703 84

Research Site

Praha 2, Czechia, 128 08

Research Site

Praha 5, Czechia, CZ-150 18

Research Site

Praha, Czechia, 140 59

France

Research Site

Avignon Cedex 09, France, 84918

Research Site

Brest Cedex, France, 29609

Research Site

Creteil, France, 94010

Research Site

La Tronche, France, 38043

Research Site

Pierre Benite Cedex, France, 69310

Research Site

Rennes Cedex 09, France, 35033

Germany

Research Site

Aachen, Germany, 52074

Research Site

Berlin, Germany, 13125

Research Site

Gauting, Germany, 82131

Research Site

Gera, Germany, 07548

Research Site

Hamburg, Germany, 20251

Research Site

Heidelberg, Germany, 69126

Research Site

Mainz, Germany, 55131

Research Site

Regensburg, Germany, 93053

Hungary

Research Site

Budapest, Hungary, 1083

Research Site

Budapest, Hungary, 1106

Research Site

Budapest, Hungary, 1121

Research Site

Budapest, Hungary, 1134

Research Site

Deszk, Hungary, 6772

Research Site

Gyula, Hungary, 5700

Research Site

Kaposvár, Hungary, 7400

Research Site

Kecskemét, Hungary, 6000

Research Site

Miskolc, Hungary, 3529

Research Site

Pécs, Hungary, 7624

Research Site

Székesfehérvár, Hungary, 8000

Israel

Research Site

Jerusalem, Israel, 91031

Research Site

Kfar Saba, Israel, 95847

Research Site

Petah Tikva, Israel, 49100

Research Site

Ramat Gan, Israel, 5265601

Italy

Research Site

Bergamo, Italy, 24127

Research Site

Meldola, Italy, 47014

Research Site

Milano, Italy, 20133

Research Site

Palermo, Italy, 90146

Research Site

Roma, Italy, 00100

Research Site

Terni, Italy, 05100

Japan

Research Site

Chuo-ku, Japan, 104-0045

Research Site

Fukuoka-shi, Japan, 812-8582

Research Site

Fukushima-shi, Japan, 960-1295

Research Site

Himeji-shi, Japan, 670-8520

Research Site

Iwakuni-shi, Japan, 740-8510

Research Site

Kashiwa, Japan, 227-8577

Research Site

Koto-ku, Japan, 135-8550

Research Site

Kurume-shi, Japan, 830-0011

Research Site

Kyoto, Japan, 606-8507

Research Site

Matsuyama-shi, Japan, 791-0280

Research Site

Nagoya-shi, Japan, 464-8681

Research Site

Nagoya-shi, Japan, 466-8560

Research Site

Okayama-shi, Japan, 700-8558

Research Site

Osakasayama, Japan, 589-8511

Research Site

Sakai-shi, Japan, 591-8555

Research Site

Tokushima-shi, Japan, 770-8503

Research Site

Ube-shi, Japan, 755-0241

Research Site

Yokohama-shi, Japan, 236-0004

Research Site

Yokohama-shi, Japan, 241-8515

Korea, Republic of

Research Site

Changwon, Korea, Republic of, 51353

Research Site

Cheongju-si, Korea, Republic of, 28644

Research Site

Daegu, Korea, Republic of, 42415

Research Site

Incheon, Korea, Republic of, 405-760

Research Site

Jinju-si, Korea, Republic of, 660-702

Research Site

Seongnam-si, Korea, Republic of, 13620

Research Site

Seongnam-si, Korea, Republic of, 463-712

Research Site

Seoul, Korea, Republic of, 05505

Research Site

Seoul, Korea, Republic of, 110746

Netherlands

Research Site

Amsterdam, Netherlands, 1066 CX

Research Site

Arnhem, Netherlands, 6815 AD

Research Site

Groningen, Netherlands, 9713 GZ

Research Site

Hengelo, Netherlands, 7555 DL

Research Site

Maastricht, Netherlands, 6202 AZ

Research Site

Rotterdam, Netherlands, 3015 GD

Poland

Research Site

Bialystok, Poland, 15-027

Research Site

Białystok, Poland, 15-540

Research Site

Lublin, Poland, 20-954

Research Site

Olsztyn, Poland, 10-357

Research Site

Warszawa, Poland, 02-781

Romania

Research Site

Cluj Napoca, Romania, 400015

Research Site

Floresti, Romania, 407280

Research Site

Suceava, Romania, 720237

Russian Federation

Research Site

Moscow, Russian Federation, 105229

Research Site

Omsk, Russian Federation, 644013

Research Site

Rostov-on-Don, Russian Federation, 344037

Research Site

Saint Petersburg, Russian Federation, 195271

Research Site

Saint-Petersburg, Russian Federation, 194291

Research Site

St. Petersburg, Russian Federation, 197758

Research Site

Ufa, Russian Federation, 450054

Slovakia

Research Site

Banska Bystrica, Slovakia, 97517

Research Site

Bardejov, Slovakia, 085 01

Research Site

Bratislava, Slovakia, 82606

Research Site

Bratislava, Slovakia, 833 01

Research Site

Kosice, Slovakia, 041 91

Research Site

Nove Zamky, Slovakia, 940 01

Research Site

Trnava, Slovakia, 91708

Spain

Research Site

A Coruña, Spain, 15006

Research Site

Badajoz, Spain, 06008

Research Site

Badalona, Spain, 08916

Research Site

Barcelona, Spain, 08041

Research Site

Madrid, Spain, 08035

Research Site

Madrid, Spain, 28040

Research Site

Madrid, Spain, 28041

Research Site

Santander, Spain, 39008

Research Site

Valencia, Spain, 46010

Research Site

Zaragoza, Spain, 50009

Taiwan

Research Site

Changhua, Taiwan, 50006

Research Site

Kaohsiung City, Taiwan, 83301

Research Site

Kaohsiung, Taiwan, 82445

Research Site

Taichung, Taiwan, 40447

Research Site

Taichung, Taiwan, 40705

Research Site

Tainan, Taiwan, 704

Research Site

Tainan, Taiwan, 736

Research Site

Taipei, Taiwan, 11217

Research Site

Taipei, Taiwan, 235

Turkey

Research Site

Ankara, Turkey, 06230

Research Site

Ankara, Turkey

Research Site

Edirne, Turkey, 22030

Research Site

Istanbul, Turkey, 34030

Research Site

Izmir, Turkey, 35100

Research Site

Izmir, Turkey, 35620

Ukraine

Research Site

Dnipro, Ukraine, 49102

Research Site

Ivano-Frankivsk, Ukraine, 76018

Research Site

Kirovohrad, Ukraine, 25006

Research Site

Kryvyi Rih, Ukraine, 50048

Research Site

Kyiv, Ukraine, 03022

Research Site

Kyiv, Ukraine, 03115

Research Site

Lviv, Ukraine, 79031

Research Site

Odesa, Ukraine, 65055

Research Site

Sumy, Ukraine, 40022

Research Site

Vinnytsia, Ukraine, 21029

Research Site

Zaporizhzhia, Ukraine, 69040

Sponsors and Collaborators

AstraZeneca

Investigators

• Study Director: Haiyi Jiang, M.D.; AstraZeneca

  Study Documents (Full-Text)

Documents provided by AstraZeneca:

Study Protocol  [PDF] January 16, 2020

Statistical Analysis Plan  [PDF] October 13, 2020

More Information

Additional Information:

Redacted CSP 

Redacted SAP 

CSPv5_redacted 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Każarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Thiyagarajah P, Jiang H, Paz-Ares L; CASPIAN investigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):51-65. doi: 10.1016/S1470-2045(20)30539-8. Epub 2020 Dec 4.

Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Ozguroglu M, Ji JH, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Kazarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Shire N, Jiang H, Goldman JW; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6. Epub 2019 Oct 4.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03043872
• Other Study ID Numbers: D419QC00001; 2016-001203-23 ( EudraCT Number )
• First Posted: February 6, 2017
• Results First Posted: March 4, 2021
• Last Update Posted: September 28, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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 request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 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 rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified 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. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

Carcinoma, Small Cell Lung; Oat Cell Carcinoma of Lung; Oat Cell Lung Cancer; Small Cell Cancer Of The Lung; Small Cell Lung Cancer

Additional relevant MeSH terms:

Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Cisplatin; Carboplatin; Etoposide; Durvalumab; Tremelimumab; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological