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

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ClinicalTrials.gov Identifier: NCT03043872
Recruitment Status : Active, not recruiting
First Posted : February 6, 2017
Results First Posted : March 4, 2021
Last Update Posted : December 21, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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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
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Layout table for study information
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 : March 29, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Durvalumab

Arms and Interventions
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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
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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
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03043872


Locations
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Sponsors and Collaborators
AstraZeneca
Investigators
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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
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Additional Information:

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

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03043872    
Other Study ID Numbers: D419QC00001
2016-001203-23 ( EudraCT Number )
First Posted: February 6, 2017    Key Record Dates
Results First Posted: March 4, 2021
Last Update Posted: December 21, 2023
Last Verified: December 2023
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

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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:
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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
Carboplatin
Etoposide
Durvalumab
Tremelimumab
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological