Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma
Conditions
Keywords
Platinum Refractory Extensive-Stage Carcinoma, Small Cell Lung, Platinum Refractory Extensive-Stage Oat Cell Carcinoma of Lung, Platinum Refractory Extensive-Stage Oat Cell Lung Cancer, Platinum Refractory Extensive-Stage Small Cell Cancer Of The Lung, Platinum Refractory Extensive-Stage Small Cell Lung Cancer
Brief summary
Study design This is a Phase II, open-label, multi-drug, multi-center, multi-arm, signal-searching study in patients with extensive-stage small-cell lung cancer (SCLC) who have refractory or resistant disease from prior platinum-based chemotherapy.
Detailed description
This study is modular in design, allowing evaluation of the preliminary efficacy, safety, tolerability, and immunogenicity of novel combinations of immunotherapies and/or deoxyribonucleic acid (DNA) damage repair inhibitors in patients with platinum refractory or resistant extensive-stage-disease SCLC. Patients who have progressive disease (PD) during first-line platinum-based chemotherapy (platinum refractory) or PD within 90 days after completing first-line platinum-based chemotherapy (platinum resistant) will be enrolled to the study. The primary objective of the study is to assess the preliminary efficacy of each treatment arm based on objective response rate (ORR). This study consists of a number of arms (sub-studies), each evaluating the efficacy, safety, and tolerability of a specific agent or combination. This study was initially open with 2 arms (Arms A and B), and additional arms may open, provided there is compelling rationale for the combination and safe and tolerable doses and schedules have been determined from ongoing Phase I studies. There are 2 pre-defined arms: A. Durvalumab + tremelimumab followed by durvalumab monotherapy B. AZD1775 + carboplatin (CBDP) Further arm was added in amendment 3: C. AZD6738 + olaparib Amendment #4 was updated with possibility to allow expansion of any arm, to a total of 40 eligible subjects, based on Review Committee assessment of data from the first 20 subjects (from Stage 1 and Stage 2). Currently Arm A will enroll 20 additional patients into expansion.
Interventions
Durvalumab + tremelimumab via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy via IV infusion q4w, starting on Week 16 until PD, or for other discontinuation criteria.
DRUGAZD1775 and carboplatin (CBPT)
AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks.
DRUGAZD6738 and olaparib
AZD6738 once a day (oral) for 7 days from Day 1 + olaparib twice a day(oral) for 28 days from Day 1, every 4 weeks
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
(applicable to all arms) * Adults with histologically or cytologically documented ED SCLC who have demonstrated progressive disease either during first-line platinum-based chemotherapy (platinum refractory) or within 90 days of completing platinum based-chemotherapy (platinum resistant) and have not received further treatment. * Brain metastases must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment. * At least 1 lesion, not previously irradiated, that can be accurately measured at baseline (per RECIST v 1.1 guidelines) * Life expectancy of at least 8 weeks. * WHO/ ECOG PS of 0-1 at enrollment. Inclusion criteria (Arm A specific) * Body weight \>30 kg. * No prior exposure to immune mediated therapy, excluding therapeutic anticancer vaccines. Inclusion criteria (Arm B specific) • Able and willing to swallow oral medication. Inclusion criteria (Arm C specific) • Able and willing to swallow oral medication.
Exclusion criteria
(applicable to all arms): * Participation in another clinical study, major surgery, radiation therapy within 28 days. * Any condition that, in the opinion of the Investigator, would interfere with the evaluation of the IP or interpretation of patient safety or study results. * Uncontrolled intercurrent illness, including but not limited to interstitial lung disease. * History of another primary malignancy, leptomeningeal carcinomatosis or spinal cord compression.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response | Until disease progression [PD] (Up to 3.5 Years) | Overall Response Rate (ORR) using Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. ORR was defined as the number (percentage) of participants with a confirmed Complete Response (CR) or confirmed Partial Response (PR) and was estimated for each treatment arm with corresponding 2-sided 95% exact confidence intervals (CIs). A confirmed response of CR/PR meant that a response of CR/PR was recorded at one visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit, and not less than 4 weeks after the visit when the response was first observed, with no evidence of progression between the initial and CR/PR confirmation visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Control at 12 Weeks | At 12 Weeks | The disease control rate (DCR) at 12 weeks was defined as the percentage of participants who had a best objective response of CR or PR in the first 13 weeks or who had demonstrated stable disease (SD) for a minimum interval of 11 weeks following the start of study treatment. The DCR was determined programmatically based on RECIST 1.1 using site Investigator data and all data up until the first progression event. |
| Time to Response (TTR) | Until disease progression or data cut-off or Death (Up to 3.5 Years) | The TTR (per RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first dose until the first date of documented response. |
| Progression Free Survival (PFS) | Until disease progression or data cut-off or Death (Up to 3.5 Years) | The PFS (per RECIST 1.1 according to the Investigator's assessment) was defined as the time from the date of the first dose of study treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from allocated therapy or received another anti-cancer therapy prior to progression. |
| Overall Survival (OS) | Until disease progression or data cut-off or Death (Up to 3.5 Years) | The OS was defined as the time from the date of the first dose of study treatment until death due to any cause. |
| Time to Maximum Concentration (Tmax) | Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) | Time to maximum concentration for ceralasertib and olaparib are reported. |
| Maximum Concentration (Cmax) | Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) | Maximum concentration for ceralasertib and olaparib are reported. |
| Partial Area Under the Concentration-time Curve (AUC0-6) | Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose) | Partial area under the concentration-time curve for ceralasertib and olaparib are reported. |
| Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) | Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose) | Area under the concentration-time curve from time zero to the last measurable concentration for Ceralasertib and Olaparib are reported. |
| Duration of Response (DoR) | Until disease progression or data cut-off or Death (Up to 3.5 Years) | The DoR was defined as the time from the date of first documented response (which was subsequently confirmed) CR/PR until the date of documented progression, or death in the absence of disease progression. The DoR in participants with confirmed objective response are reported. |
| Maximum Concentration at Steady State (Cmax,ss) | Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose) | Maximum concentration at steady state for Ceralasertib and Olaparib are reported. |
| Minimum Concentration at Steady State (Cmin,ss) | Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose) | Minimum concentration at steady state for Ceralasertib and Olaparib are reported. |
| Area Under the Concentration-time Curve at Steady State (AUCss) | Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose) | Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported. |
| Apparent Clearance of Drug at Steady State at Steady State (CLss/F) | Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose) | Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported. |
| Serum Concentrations of Durvalumab and Tremelimumab | Durvalumab: Cycle 1 (each cycle was 4 weeks) Day 1(post-dose); Cycle 2 Day 1(pre-dose); Cycle 5 Day 1 (pre-dose); Tremelimumab: Cycle 1 (each cycle was 4 weeks) Day 1 (post-dose); Cycle 2 Day 1 (pre-dose); Cycle 5 Day 1 (No dose); Cycle 7 Day 1 (No dose) | Serum concentrations of Durvalumab and Tremelimumab are reported. |
| Plasma Concentrations of Adavosertib and Carboplatin | Adavosertib: Cycle 1 (each cycle was 21 days) Day 3 (pre-dose and post-dose); Cycle 3 Day 3 (pre-dose and post-dose); Carboplatin: Cycle 1 (each cycle was 21 days) Day 1 (post-dose) | Plasma concentrations of Adavosertib and Carboplatin are reported. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 until disease progression, and follow-up visit (Up to 3.5 Years) | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. SAE is an AE that results in any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a significant medical event. |
| Time to Maximum Concentration at Steady State (Tmax,ss) | Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose) | Time to maximum concentration at steady state for Ceralasertib and Olaparib are reported. |
Countries
Germany, Hungary, Poland, Spain, Ukraine
Participant flow
Recruitment details
The study was conducted between 28-Nov-2016 and 22-Jun-2020, at 11 study centers in 5 countries (Germany, Hungary, Poland, Spain, and Ukraine).
Pre-assignment details
Participants who met the inclusion exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) Participants received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed progressive disease (PD), or other discontinuation criteria. | 21 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Participants received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed PD, or other discontinuation criteria. | 20 |
| Arm B: Adavosertib + Carboplatin Participants orally received adavosertib 225 mg twice daily (BID) for 2.5 days from Day 1 + carboplatin area under the curve (AUC) 5 Day 1 IV, every 3 weeks (q3w). | 10 |
| Arm C: Ceralasertib (AZD6738) + Olaparib Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w. | 21 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 1 | 1 |
| Overall Study | Condition under investigation worsened | 0 | 0 | 1 | 0 |
| Overall Study | Disease progression | 17 | 15 | 7 | 19 |
| Overall Study | Participants decision | 2 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm A: Durvalumab + Tremelimumab (Original Cohort) | Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Arm B: Adavosertib + Carboplatin | Arm C: Ceralasertib (AZD6738) + Olaparib | Total |
|---|---|---|---|---|---|
| Age, Customized < 50 | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Age, Customized ≥ 50 to < 65 | 13 Participants | 12 Participants | 5 Participants | 12 Participants | 42 Participants |
| Age, Customized ≥ 65 to < 75 | 6 Participants | 6 Participants | 3 Participants | 5 Participants | 20 Participants |
| Age, Customized ≥ 75 to < 80 | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Age, Customized ≥ 80 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 19 Participants | 10 Participants | 21 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 20 Participants | 10 Participants | 21 Participants | 72 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 2 Participants | 7 Participants | 19 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 8 Participants | 14 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 19 / 21 | 16 / 20 | 10 / 10 | 15 / 21 |
| other Total, other adverse events | 14 / 21 | 16 / 20 | 8 / 10 | 13 / 21 |
| serious Total, serious adverse events | 6 / 21 | 8 / 20 | 4 / 10 | 7 / 21 |
Outcome results
Primary
Number of Participants With Overall Response
Overall Response Rate (ORR) using Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. ORR was defined as the number (percentage) of participants with a confirmed Complete Response (CR) or confirmed Partial Response (PR) and was estimated for each treatment arm with corresponding 2-sided 95% exact confidence intervals (CIs). A confirmed response of CR/PR meant that a response of CR/PR was recorded at one visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit, and not less than 4 weeks after the visit when the response was first observed, with no evidence of progression between the initial and CR/PR confirmation visit.
Time frame: Until disease progression [PD] (Up to 3.5 Years)
Population: The FAS included all treated participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Number of Participants With Overall Response | 2 Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Number of Participants With Overall Response | 1 Participants |
| Arm B: Adavosertib + Carboplatin | Number of Participants With Overall Response | 0 Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Number of Participants With Overall Response | 1 Participants |
Secondary
Apparent Clearance of Drug at Steady State at Steady State (CLss/F)
Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Apparent Clearance of Drug at Steady State at Steady State (CLss/F) | NA Litre/hour | — |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Apparent Clearance of Drug at Steady State at Steady State (CLss/F) | 4.416 Litre/hour | Geometric Coefficient of Variation 42.3171 |
Secondary
Area Under the Concentration-time Curve at Steady State (AUCss)
Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Area Under the Concentration-time Curve at Steady State (AUCss) | NA h*µg/mL | — |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Area Under the Concentration-time Curve at Steady State (AUCss) | 67.929 h*µg/mL | Geometric Coefficient of Variation 37.4297 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t)
Area under the concentration-time curve from time zero to the last measurable concentration for Ceralasertib and Olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses. Here, number analyzed in each row signifies only participants with available data that were analyzed for that specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) | Cycle 1, Day 1 | 18.575 h*µg/mL | Geometric Coefficient of Variation 34.5074 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) | Cycle 1, Day 7 | 24.061 h*µg/mL | Geometric Coefficient of Variation 23.0923 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) | Cycle 1, Day 1 | 26.973 h*µg/mL | Geometric Coefficient of Variation 41.4461 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) | Cycle 1, Day 7 | 62.535 h*µg/mL | Geometric Coefficient of Variation 42.4552 |
Secondary
Duration of Response (DoR)
The DoR was defined as the time from the date of first documented response (which was subsequently confirmed) CR/PR until the date of documented progression, or death in the absence of disease progression. The DoR in participants with confirmed objective response are reported.
Time frame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
Population: The FAS included all treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Duration of Response (DoR) | NA Months |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Duration of Response (DoR) | 3 Months |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Duration of Response (DoR) | 8.5 Months |
Secondary
Maximum Concentration at Steady State (Cmax,ss)
Maximum concentration at steady state for Ceralasertib and Olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Maximum Concentration at Steady State (Cmax,ss) | 5.176 µg/mL | Geometric Coefficient of Variation 23.4058 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Maximum Concentration at Steady State (Cmax,ss) | 9.189 µg/mL | Geometric Coefficient of Variation 30.4888 |
Secondary
Maximum Concentration (Cmax)
Maximum concentration for ceralasertib and olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Maximum Concentration (Cmax) | 4.215 µg/mL | Geometric Coefficient of Variation 27.7129 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Maximum Concentration (Cmax) | 6.558 µg/mL | Geometric Coefficient of Variation 39.9411 |
Secondary
Minimum Concentration at Steady State (Cmin,ss)
Minimum concentration at steady state for Ceralasertib and Olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Minimum Concentration at Steady State (Cmin,ss) | 1.119 µg/mL | Geometric Coefficient of Variation 55.907 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Minimum Concentration at Steady State (Cmin,ss) | 2.376 µg/mL | Geometric Coefficient of Variation 61.8191 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. SAE is an AE that results in any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a significant medical event.
Time frame: Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Population: The FAS included all treated participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 6 Participants |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 16 Participants |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of any study treatment | 2 Participants |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE with outcome = death | 1 Participants |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE causally related to any study treatment | 10 Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE with outcome = death | 0 Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 8 Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of any study treatment | 4 Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE causally related to any study treatment | 9 Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 17 Participants |
| Arm B: Adavosertib + Carboplatin | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE with outcome = death | 1 Participants |
| Arm B: Adavosertib + Carboplatin | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 8 Participants |
| Arm B: Adavosertib + Carboplatin | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE causally related to any study treatment | 8 Participants |
| Arm B: Adavosertib + Carboplatin | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 4 Participants |
| Arm B: Adavosertib + Carboplatin | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of any study treatment | 1 Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 7 Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE causally related to any study treatment | 16 Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 18 Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE with outcome = death | 1 Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of any study treatment | 1 Participants |
Secondary
Overall Survival (OS)
The OS was defined as the time from the date of the first dose of study treatment until death due to any cause.
Time frame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
Population: The FAS included all treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Overall Survival (OS) | 5.95 Months |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Overall Survival (OS) | 3.37 Months |
| Arm B: Adavosertib + Carboplatin | Overall Survival (OS) | 4.67 Months |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Overall Survival (OS) | 7.56 Months |
Secondary
Partial Area Under the Concentration-time Curve (AUC0-6)
Partial area under the concentration-time curve for ceralasertib and olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses. Here, number analyzed in each row signifies only participants with available data that were analyzed for that specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Partial Area Under the Concentration-time Curve (AUC0-6) | Cycle 1, Day 1 | 18.346 h*µg/mL | Geometric Coefficient of Variation 34.6952 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Partial Area Under the Concentration-time Curve (AUC0-6) | Cycle 1, Day 7 | 23.666 h*µg/mL | Geometric Coefficient of Variation 23.9202 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Partial Area Under the Concentration-time Curve (AUC0-6) | Cycle 1, Day 1 | 26.356 h*µg/mL | Geometric Coefficient of Variation 42.2963 |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Partial Area Under the Concentration-time Curve (AUC0-6) | Cycle 1, Day 7 | 42.016 h*µg/mL | Geometric Coefficient of Variation 33.7599 |
Secondary
Percentage of Participants With Disease Control at 12 Weeks
The disease control rate (DCR) at 12 weeks was defined as the percentage of participants who had a best objective response of CR or PR in the first 13 weeks or who had demonstrated stable disease (SD) for a minimum interval of 11 weeks following the start of study treatment. The DCR was determined programmatically based on RECIST 1.1 using site Investigator data and all data up until the first progression event.
Time frame: At 12 Weeks
Population: The FAS included all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Percentage of Participants With Disease Control at 12 Weeks | 38.1 Percentage of Participants |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Percentage of Participants With Disease Control at 12 Weeks | 15.0 Percentage of Participants |
| Arm B: Adavosertib + Carboplatin | Percentage of Participants With Disease Control at 12 Weeks | 30.0 Percentage of Participants |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Percentage of Participants With Disease Control at 12 Weeks | 38.1 Percentage of Participants |
Secondary
Plasma Concentrations of Adavosertib and Carboplatin
Plasma concentrations of Adavosertib and Carboplatin are reported.
Time frame: Adavosertib: Cycle 1 (each cycle was 21 days) Day 3 (pre-dose and post-dose); Cycle 3 Day 3 (pre-dose and post-dose); Carboplatin: Cycle 1 (each cycle was 21 days) Day 1 (post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses. Here, number analyzed in each row signifies only participants with available data that were analyzed for that specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Plasma Concentrations of Adavosertib and Carboplatin | Adavosertib: Cycle 1 Day 3 (Pre-dose) | 551.489 nM | Geometric Coefficient of Variation 41.5823 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Plasma Concentrations of Adavosertib and Carboplatin | Adavosertib: Cycle 1 Day 3 (Post-dose) | 728.342 nM | Geometric Coefficient of Variation 62.3968 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Plasma Concentrations of Adavosertib and Carboplatin | Adavosertib: Cycle 3 Day 3 (Pre-dose) | 606.571 nM | Geometric Coefficient of Variation 46.7716 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Plasma Concentrations of Adavosertib and Carboplatin | Adavosertib: Cycle 3 Day 3 (Post-dose) | 805.270 nM | Geometric Coefficient of Variation 68.0275 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Plasma Concentrations of Adavosertib and Carboplatin | Carboplatin: Cycle 1 Day 1 (Post-dose) | 12834.615 nM | Geometric Coefficient of Variation 27.5493 |
Secondary
Progression Free Survival (PFS)
The PFS (per RECIST 1.1 according to the Investigator's assessment) was defined as the time from the date of the first dose of study treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from allocated therapy or received another anti-cancer therapy prior to progression.
Time frame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
Population: The FAS included all treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Progression Free Survival (PFS) | 1.91 Months |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Progression Free Survival (PFS) | 1.77 Months |
| Arm B: Adavosertib + Carboplatin | Progression Free Survival (PFS) | 2.60 Months |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Progression Free Survival (PFS) | 2.92 Months |
Secondary
Serum Concentrations of Durvalumab and Tremelimumab
Serum concentrations of Durvalumab and Tremelimumab are reported.
Time frame: Durvalumab: Cycle 1 (each cycle was 4 weeks) Day 1(post-dose); Cycle 2 Day 1(pre-dose); Cycle 5 Day 1 (pre-dose); Tremelimumab: Cycle 1 (each cycle was 4 weeks) Day 1 (post-dose); Cycle 2 Day 1 (pre-dose); Cycle 5 Day 1 (No dose); Cycle 7 Day 1 (No dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses. Here, number analyzed in each row signifies only participants with available data that were analyzed for that specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Durvalumab: Cycle 1 Day 1 (Post-dose) | 391.192 μg/mL | Geometric Coefficient of Variation 23.599 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Durvalumab: Cycle 2 Day 1 (Pre-dose) | 55.590 μg/mL | Geometric Coefficient of Variation 53.0745 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Durvalumab: Cycle 5 Day 1 (Pre-dose) | 116.846 μg/mL | Geometric Coefficient of Variation 51.0036 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Tremelimumab: Cycle 1 Day 1 (Post-dose) | 18.299 μg/mL | Geometric Coefficient of Variation 20.8181 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Tremelimumab: Cycle 2 Day 1 (Pre-dose) | 2.650 μg/mL | Geometric Coefficient of Variation 53.1007 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Tremelimumab: Cycle 5 Day 1 (No dose) | 5.005 μg/mL | Geometric Coefficient of Variation 38.3784 |
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Serum Concentrations of Durvalumab and Tremelimumab | Tremelimumab: Cycle 7 Day 1 (No dose) | 0.784 μg/mL | Geometric Coefficient of Variation 66.3469 |
Secondary
Time to Maximum Concentration at Steady State (Tmax,ss)
Time to maximum concentration at steady state for Ceralasertib and Olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Time to Maximum Concentration at Steady State (Tmax,ss) | 1.875 Hour |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Time to Maximum Concentration at Steady State (Tmax,ss) | 2.708 Hour |
Secondary
Time to Maximum Concentration (Tmax)
Time to maximum concentration for ceralasertib and olaparib are reported.
Time frame: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
Population: Pharmacokinetic Analysis Set: all participants who received at least 1 dose of study treatment and had post-dose data available, excluding those who had a deviation considered by the sponsor to have a potential impact on the interpretation of the pharmacokinetic analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Time to Maximum Concentration (Tmax) | 1.250 Hour |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Time to Maximum Concentration (Tmax) | 1.800 Hour |
Secondary
Time to Response (TTR)
The TTR (per RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first dose until the first date of documented response.
Time frame: Until disease progression or data cut-off or Death (Up to 3.5 Years)
Population: The FAS included all treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Durvalumab + Tremelimumab (Original Cohort) | Time to Response (TTR) | 1.8 Months |
| Arm A: Durvalumab + Tremelimumab (Expansion Cohort) | Time to Response (TTR) | 1.8 Months |
| Arm C: Ceralasertib (AZD6738) + Olaparib | Time to Response (TTR) | 1.7 Months |