Trial Outcomes & Findings for A Phase II, Study to Determine the Preliminary Efficacy of Novel Combinations of Treatment in Patients With Platinum Refractory Extensive-Stage Small-Cell Lung Cancer (NCT NCT02937818)

Last Updated: 2024-06-07

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

72 participants

Primary outcome timeframe

Until disease progression [PD] (Up to 3.5 Years)

Results posted on

2024-06-07

Participant Flow

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).

Participants who met the inclusion exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.

Participant milestones

Participant milestones
Measure	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.	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.	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).	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.
Overall Study STARTED	21	20	10	21
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	21	20	10	21

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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).	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.
Overall Study Participants decision	2	1	1	1
Overall Study Adverse Event	2	4	1	1
Overall Study Disease progression	17	15	7	19
Overall Study Condition under investigation worsened	0	0	1	0

Baseline Characteristics

A Phase II, Study to Determine the Preliminary Efficacy of Novel Combinations of Treatment in Patients With Platinum Refractory Extensive-Stage Small-Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 Participants 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.	Arm B: Adavosertib + Carboplatin n=10 Participants 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.	Total n=72 Participants Total of all reporting groups
Age, Customized < 50	2 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	2 Participants n=483 Participants	5 Participants n=36 Participants
Age, Customized ≥ 50 to < 65	13 Participants n=93 Participants	12 Participants n=4 Participants	5 Participants n=27 Participants	12 Participants n=483 Participants	42 Participants n=36 Participants
Age, Customized ≥ 65 to < 75	6 Participants n=93 Participants	6 Participants n=4 Participants	3 Participants n=27 Participants	5 Participants n=483 Participants	20 Participants n=36 Participants
Age, Customized ≥ 75 to < 80	0 Participants n=93 Participants	2 Participants n=4 Participants	1 Participants n=27 Participants	2 Participants n=483 Participants	5 Participants n=36 Participants
Age, Customized ≥ 80	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Sex: Female, Male Female	6 Participants n=93 Participants	4 Participants n=4 Participants	2 Participants n=27 Participants	7 Participants n=483 Participants	19 Participants n=36 Participants
Sex: Female, Male Male	15 Participants n=93 Participants	16 Participants n=4 Participants	8 Participants n=27 Participants	14 Participants n=483 Participants	53 Participants n=36 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	1 Participants n=36 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants n=93 Participants	19 Participants n=4 Participants	10 Participants n=27 Participants	21 Participants n=483 Participants	71 Participants n=36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) White	21 Participants n=93 Participants	20 Participants n=4 Participants	10 Participants n=27 Participants	21 Participants n=483 Participants	72 Participants n=36 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants

PRIMARY outcome

Timeframe: Until disease progression [PD] (Up to 3.5 Years)

Population: The FAS included all treated participants.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 Participants 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.	Arm B: Adavosertib + Carboplatin n=10 Participants 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Number of Participants With Overall Response	2 Participants	1 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Until disease progression or data cut-off or Death (Up to 3.5 Years)

Population: The FAS included all treated participants.

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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=2 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=1 Participants 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.	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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=1 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Duration of Response (DoR)	NA Months Interval 1.5 to Objective response not reached	3 Months Interval 3.0 to 3.0	—	8.5 Months Interval 8.5 to 8.5

SECONDARY outcome

Timeframe: At 12 Weeks

Population: The FAS included all treated participants.

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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 Participants 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.	Arm B: Adavosertib + Carboplatin n=10 Participants 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Percentage of Participants With Disease Control at 12 Weeks	38.1 Percentage of Participants	15.0 Percentage of Participants	30.0 Percentage of Participants	38.1 Percentage of Participants

SECONDARY outcome

Timeframe: Until disease progression or data cut-off or Death (Up to 3.5 Years)

Population: The FAS included all treated participants.

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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=2 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=1 Participants 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.	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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=1 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Time to Response (TTR)	1.8 Months Interval 1.7 to 1.8	1.8 Months Interval 1.8 to 1.8	—	1.7 Months Interval 1.7 to 1.7

SECONDARY outcome

Timeframe: Until disease progression or data cut-off or Death (Up to 3.5 Years)

Population: The FAS included all treated participants.

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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 Participants 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.	Arm B: Adavosertib + Carboplatin n=10 Participants 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Progression Free Survival (PFS)	1.91 Months Interval 1.77 to 4.34	1.77 Months Interval 1.02 to 2.2	2.60 Months Interval 0.56 to 4.83	2.92 Months Interval 1.81 to 4.53

SECONDARY outcome

Timeframe: Until disease progression or data cut-off or Death (Up to 3.5 Years)

Population: The FAS included all treated participants.

The OS was defined as the time from the date of the first dose of study treatment until death due to any cause.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 Participants 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.	Arm B: Adavosertib + Carboplatin n=10 Participants 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Overall Survival (OS)	5.95 Months Interval 1.91 to 10.61	3.37 Months Interval 1.91 to 7.66	4.67 Months Interval 0.56 to 5.98	7.56 Months Interval 4.21 to 12.58

SECONDARY outcome

Timeframe: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)

Time to maximum concentration for ceralasertib and olaparib are reported.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=21 Participants 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.	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).	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.
Time to Maximum Concentration (Tmax)	1.250 Hour Interval 1.0 to 6.08	1.800 Hour Interval 1.0 to 6.08	—	—

SECONDARY outcome

Timeframe: Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)

Maximum concentration for ceralasertib and olaparib are reported.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=21 Participants 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.	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).	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.
Maximum Concentration (Cmax)	4.215 µg/mL Geometric Coefficient of Variation 27.7129	6.558 µg/mL Geometric Coefficient of Variation 39.9411	—	—

SECONDARY outcome

Timeframe: 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.

Partial area under the concentration-time curve for ceralasertib and olaparib are reported.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=20 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=21 Participants 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.	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).	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.
Partial Area Under the Concentration-time Curve (AUC0-6) Cycle 1, Day 1	18.346 h*µg/mL Geometric Coefficient of Variation 34.6952	26.356 h*µg/mL Geometric Coefficient of Variation 42.2963	—	—
Partial Area Under the Concentration-time Curve (AUC0-6) Cycle 1, Day 7	23.666 h*µg/mL Geometric Coefficient of Variation 23.9202	42.016 h*µg/mL Geometric Coefficient of Variation 33.7599	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=21 Participants 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.	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).	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.
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	26.973 h*µg/mL Geometric Coefficient of Variation 41.4461	—	—
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	62.535 h*µg/mL Geometric Coefficient of Variation 42.4552	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=10 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=10 Participants 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.	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).	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.
Time to Maximum Concentration at Steady State (Tmax,ss)	1.875 Hour Interval 0.63 to 6.08	2.708 Hour Interval 0.63 to 4.5	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=10 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=10 Participants 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.	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).	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.
Maximum Concentration at Steady State (Cmax,ss)	5.176 µg/mL Geometric Coefficient of Variation 23.4058	9.189 µg/mL Geometric Coefficient of Variation 30.4888	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=10 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=10 Participants 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.	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).	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.
Minimum Concentration at Steady State (Cmin,ss)	1.119 µg/mL Geometric Coefficient of Variation 55.9070	2.376 µg/mL Geometric Coefficient of Variation 61.8191	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=10 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=9 Participants 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.	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).	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.
Area Under the Concentration-time Curve at Steady State (AUCss)	NA h*µg/mL Geometric Coefficient of Variation NA There were not enough pharmacokinetic data points collected to calculate AUCss	67.929 h*µg/mL Geometric Coefficient of Variation 37.4297	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=10 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=9 Participants 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.	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).	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.
Apparent Clearance of Drug at Steady State at Steady State (CLss/F)	NA Litre/hour Geometric Coefficient of Variation NA There were not enough pharmacokinetic data points collected to calculate CLss/F	4.416 Litre/hour Geometric Coefficient of Variation 42.3171	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	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.	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).	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.
Serum Concentrations of Durvalumab and Tremelimumab Durvalumab: Cycle 1 Day 1 (Post-dose)	391.192 μg/mL Geometric Coefficient of Variation 23.5990	—	—	—
Serum Concentrations of Durvalumab and Tremelimumab Durvalumab: Cycle 2 Day 1 (Pre-dose)	55.590 μg/mL Geometric Coefficient of Variation 53.0745	—	—	—
Serum Concentrations of Durvalumab and Tremelimumab Durvalumab: Cycle 5 Day 1 (Pre-dose)	116.846 μg/mL Geometric Coefficient of Variation 51.0036	—	—	—
Serum Concentrations of Durvalumab and Tremelimumab Tremelimumab: Cycle 1 Day 1 (Post-dose)	18.299 μg/mL Geometric Coefficient of Variation 20.8181	—	—	—
Serum Concentrations of Durvalumab and Tremelimumab Tremelimumab: Cycle 2 Day 1 (Pre-dose)	2.650 μg/mL Geometric Coefficient of Variation 53.1007	—	—	—
Serum Concentrations of Durvalumab and Tremelimumab Tremelimumab: Cycle 5 Day 1 (No dose)	5.005 μg/mL Geometric Coefficient of Variation 38.3784	—	—	—
Serum Concentrations of Durvalumab and Tremelimumab Tremelimumab: Cycle 7 Day 1 (No dose)	0.784 μg/mL Geometric Coefficient of Variation 66.3469	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=10 Participants 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.	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.	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).	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.
Plasma Concentrations of Adavosertib and Carboplatin Adavosertib: Cycle 1 Day 3 (Pre-dose)	551.489 nM Geometric Coefficient of Variation 41.5823	—	—	—
Plasma Concentrations of Adavosertib and Carboplatin Adavosertib: Cycle 1 Day 3 (Post-dose)	728.342 nM Geometric Coefficient of Variation 62.3968	—	—	—
Plasma Concentrations of Adavosertib and Carboplatin Adavosertib: Cycle 3 Day 3 (Pre-dose)	606.571 nM Geometric Coefficient of Variation 46.7716	—	—	—
Plasma Concentrations of Adavosertib and Carboplatin Adavosertib: Cycle 3 Day 3 (Post-dose)	805.270 nM Geometric Coefficient of Variation 68.0275	—	—	—
Plasma Concentrations of Adavosertib and Carboplatin Carboplatin: Cycle 1 Day 1 (Post-dose)	12834.615 nM Geometric Coefficient of Variation 27.5493	—	—	—

SECONDARY outcome

Timeframe: Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)

Population: The FAS included all treated participants.

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.

Outcome measures

Outcome measures
Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 Participants 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 Participants 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.	Arm B: Adavosertib + Carboplatin n=10 Participants 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 Participants Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE	16 Participants	17 Participants	8 Participants	18 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE causally related to any study treatment	10 Participants	9 Participants	8 Participants	16 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE with outcome = death	1 Participants	0 Participants	1 Participants	1 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any SAE	6 Participants	8 Participants	4 Participants	7 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE leading to discontinuation of any study treatment	2 Participants	4 Participants	1 Participants	1 Participants

Adverse Events

Arm A: Durvalumab + Tremelimumab (Original Cohort)

Serious events: 6 serious events

Other events: 14 other events

Deaths: 19 deaths

Arm A: Durvalumab + Tremelimumab (Expansion Cohort)

Serious events: 8 serious events

Other events: 16 other events

Deaths: 16 deaths

Arm B: Adavosertib + Carboplatin

Serious events: 4 serious events

Other events: 8 other events

Deaths: 10 deaths

Arm C: Ceralasertib (AZD6738) + Olaparib

Serious events: 7 serious events

Other events: 13 other events

Deaths: 15 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca Clinical Study Information Center

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Study results are Sponsor's intellectual property and PIs cannot present or publish results without prior Sponsor approval.
Publication restrictions are in place

Restriction type: OTHER

Measure	Arm A: Durvalumab + Tremelimumab (Original Cohort) n=21 participants at risk 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.	Arm A: Durvalumab + Tremelimumab (Expansion Cohort) n=20 participants at risk 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.	Arm B: Adavosertib + Carboplatin n=10 participants at risk 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).	Arm C: Ceralasertib (AZD6738) + Olaparib n=21 participants at risk Participants orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
Infections and infestations Gastroenteritis	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Infections and infestations Pneumonia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Blood and lymphatic system disorders Anaemia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	19.0% 4/21 • Number of events 5 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Nervous system disorders Myasthenic syndrome	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Nervous system disorders Peripheral sensory neuropathy	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Gastrointestinal disorders Abdominal pain	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Gastrointestinal disorders Colitis	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Gastrointestinal disorders Diarrhoea	9.5% 2/21 • Number of events 2 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	10.0% 1/10 • Number of events 3 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Gastrointestinal disorders Enterocolitis haemorrhagic	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Gastrointestinal disorders Pancreatitis	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Investigations Hepatic enzyme increased	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Injury, poisoning and procedural complications Burns third degree	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Injury, poisoning and procedural complications Femoral neck fracture	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Injury, poisoning and procedural complications Femur fracture	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	5.0% 1/20 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Injury, poisoning and procedural complications Toxicity to various agents	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	10.0% 1/10 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Blood and lymphatic system disorders Haematotoxicity	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	10.0% 1/10 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Blood and lymphatic system disorders Pancytopenia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	10.0% 1/10 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
Infections and infestations Urinary tract infection	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	4.8% 1/21 • Number of events 2 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
General disorders Asthenia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
General disorders Pyrexia	0.00% 0/21 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/20 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	0.00% 0/10 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)	4.8% 1/21 • Number of events 1 • Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)