Efficacy and Safety Study of cediranib in combination with olaparib in Patients with Recurrent Platinum-Resistant Ovarian Cancer - CONCERTO

Study identifier:D8488C00001

ClinicalTrials.gov identifier:NCT02889900

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A single arm, open-label, Phase IIb study to assess the efficacy and safety of the combination of cediranib and olaparib tablets in women with recurrent platinum resistant epithelial ovarian cancer, including fallopian tube and/or primary peritoneal cancer who do not carry a deleterious or suspected deleterious germline BRCA mutation

Medical condition

recurrent platinum resistant ovarian cancer

Phase

Phase 2

Healthy volunteers

Study drug

cediranib and olaparib

Sex

Female

Actual Enrollment

Study type

Interventional

Age

18 Years - 120 Years

Date

Study Start Date: 17 Jan 2017

Primary Completion Date: 27 Aug 2019

Study Completion Date: 16 Mar 2021

Study design

Allocation: N/A
Endpoint Classification: Safety/Efficacy
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2022 by AstraZeneca

Collaborators

Myriad Genetic Laboratories, Inc., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc

Inclusion and exclusion criteria

Inclusion Criteria

1.Ability and willingness to provide written informed consent, and to comply with the requirements of the protocol
2.Females aged ≥18 years with previous histologically proven diagnosis of high grade serous, high grade endometroid or clear cell ovarian cancer, fallopian tube or primary peritoneal carcinoma
3.No evidence of deleterious or suspected deleterious germline mutation in BRCA1 or BRCA2 genes
4.Recurrent platinum-resistant disease, defined as disease progression within 6 months (182 days) of the last receipt of platinum-based chemotherapy
5.CT/MRI evidence of measurable disease as per RECIST 1.1 defined as at least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) and which is suitable for accurate repeated measurements
6.Eastern Cooperative Oncology Group (ECOG) performance status 0-2
7.Life expectancy ≥12 weeks
8.Prior receipt of antiangiogenic treatment, including but not limited to bevacizumab, is optional. If used, it can be used in the first line or recurrent setting.
9.At least three prior lines of therapy for advanced ovarian cancer as defined in the protocol
10.Confirmation of the availability of a tumor sample from the primary or recurrent cancer must be provided
11.Patients must have adequate organ and bone marrow function
12.Adequately controlled blood pressure
13.Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
14.Able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption of cediranib or olaparib
15.Postmenopausal or evidence of non-childbearing status for women of childbearing potential as confirmed by a negative urine or serum pregnancy test within 7 days prior to start of IPs

Exclusion Criteria

1.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
2.Previous enrollment in the present study.
3.Exposure to any IP during the last 4 weeks prior to enrollment.
4.Previous treatment with PARP inhibitor. For this study, BSI-201 (iniparib) is not considered as PARPi
5.Recent cancer-directed therapies: Radiotherapy (RT) within 4 weeks, chemotherapy or other systemic anti-cancer therapy within 4 weeks, or prior anti-angiogenic treatment (e.g., bevacizumab) within 6 weeks prior to starting treatment
6.Cancer antigen-125 (CA-125) only disease without RECIST 1.1 measurable disease
7.Major surgical procedure within 2 weeks prior to starting treatment; patients must have recovered from any effects of any major surgery and surgical wound should have healed prior to starting treatment
8.Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment
9.History of intra-abdominal abscess within 3 months prior to starting treatment
10.History of GI perforation. Patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting treatment, and patient is deemed to be at low risk of recurrent fistula
11.Other malignancy within the last 5 years
12.Persisting ≥Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral neuropathy) from previous anti-cancer treatment(s)
13.Central nervous system metastases
14.Patients with any of the following: History of myocardial infarction within 6 months prior to starting treatment; Unstable angina; Resting electrocardiogram (ECG) with clinically significant abnormal findings; New York Heart Association functional classification of III or IV
15.Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per institutional guidelines, or <55%, if threshold for normal not otherwise specified by institutional guidelines, for patients with the following risk factors: Prior treatment with anthracyclines; Prior treatment with trastuzumab; Prior central thoracic RT, including exposure of heart to therapeutic doses of ionizing RT; History of myocardial infarction within 6-12 months prior to start of IPs; Prior history of other significant impaired cardiac function
16.History of stroke or transient ischemic attack within 6 months
17.Uncontrolled intercurrent illness
18.Patients with myelodysplastic syndrome (MDS)/ treatment-related acute myeloid leukemia (t-AML) or with features suggestive of MDS/AML
19.No prior allogenic bone marrow transplant or double umbilical cord blood transplantation
20.Known active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection on antiviral treatment
21.Concomitant use of known strong or moderate CYP3A inhibitors
22.Concomitant use of known strong or moderate CYP3A inducers

Location

Research Site

Orange, CA, United States, 92868

Location

Research Site

Covington, LA, United States, 70433

Location

Research Site

West Hollywood, CA, United States, 90048

Location

Research Site

Greenbrae, CA, United States, 94904

Location

Research Site

Orlando, FL, United States, 32804

Location

Research Site

San Diego, CA, United States, 92123

Location

Research Site

Westwood, KS, United States, 66205

Location

Research Site

Downey, CA, United States, 90241

Arms	Assigned Interventions
Experimental: combination of cediranib and olaparib Open label	Drug: cediranib and olaparib Cediranib tablets oral dose 30 mg once daily; Olaparib(Lynparza) tablet 200 mg twice daily Dose reduction for both products is allowed Other Name: Olaparib: also known as Lynparza

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients with platinum-resistant relapsed high grade serous, high grade endometroid or clear cell ovarian, fallopian tube or primary peritoneal carcinoma who had received at least 3 prior lines of therapy for advanced ovarian cancer were recruited to 25 study centers in the United States in this single arm, open-label Phase IIb study.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients had no evidence of deleterious or suspected deleterious germline breast cancer susceptibility gene (gBRCA) mutations. Patients had to have measurable disease, defined as ≥1 lesion that could be assessed at baseline by computed tomography / magnetic resonance imaging and be suitable for repeated assessment.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 milligrams (mg) orally once daily (qd) and olaparib 200 mg orally twice daily (bid) until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Participant Flow: Overall Study

	Cediranib + Olaparib
STARTED	62
Received treatment	60
COMPLETED	5^[1]
NOT COMPLETED	57
Adverse Event	11
Condition under investigation worsened	32
Not specified	5
Withdrawal by Subject	7
Not treated	2

[1]	Patients ongoing in study at primary analysis data cut off (DCO)

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The Full analysis set (FAS) included all patients who received at least 1 dose of either of the investigational products (IPs).

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Baseline Measures

	Cediranib + Olaparib
Number of Participants [units: Participants]	60
Age Continuous [units: years] Mean ± Standard Deviation	63.8 ± 8.65
Sex: Female, Male [units: participants]
Female	60
Male	0
Race/Ethnicity, Customized [units: participants]
White	55
Asian	2
Other	3
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	5
Not Hispanic or Latino	54
Unknown or Not Reported	1

Outcome Measures

1. Primary Outcome Measure: Mean Objective Response Rate (ORR) by Independent Central Review (ICR) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. ]

Measure Type	Primary
Measure Name	Mean Objective Response Rate (ORR) by Independent Central Review (ICR) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Measure Description	The ORR was defined as the percentage of patients with objective response (complete response [CR] or partial response [PR]) according to RECIST 1.1 and was assessed by ICR. Only patients whose CR/PR response was confirmed by a second scan at least 4 weeks after the initial response, with no evidence of progression between the initial and CR/PR confirmation visit were included. CR: Disappearance of all target lesions (TLs) and non-TLs (NTLS) since baseline; any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 millimeters (mm). PR: At least a 30% decrease in the sum of the diameters of TL, referencing the baseline sum of diameters. Data obtained up until progression, or last evaluable assessment in the absence of progression were included in the assessment of ORR.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The evaluable for response (EFR) analysis set included all patients who received at least 1 dose of IP and had measurable disease at baseline according to the independent review of baseline imaging data. RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	59
Mean Objective Response Rate (ORR) by Independent Central Review (ICR) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [units: percentage of patients] Number (95% Confidence Interval)	15.3 (7.2 to 27.0)

No statistical analysis provided for Mean Objective Response Rate (ORR) by Independent Central Review (ICR) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

2. Secondary Outcome Measure: ORR by Investigator Assessment Using RECIST 1.1 [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. ]

Measure Type	Secondary
Measure Name	ORR by Investigator Assessment Using RECIST 1.1
Measure Description	The percentage of patients with a response (CR/PR), including patients with both confirmed and unconfirmed responses, based on investigator assessed RECIST 1.1 data is presented. Confirmed responses included patients whose CR/PR response was confirmed by a second scan at least 4 weeks after the initial response, with no evidence of progression between the initial and CR/PR confirmation visit. CR: Disappearance of all TLs and NTLs since baseline; any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of TL, referencing the baseline sum of diameters.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all patients who received at least 1 dose of either of the IPs.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	60
ORR by Investigator Assessment Using RECIST 1.1 [units: percentage of patients] Number (95% Confidence Interval)	26.7 (16.1 to 39.7)

No statistical analysis provided for ORR by Investigator Assessment Using RECIST 1.1

3. Secondary Outcome Measure: Median Duration of Response (DoR) by ICR and Investigator Assessment Using RECIST 1.1 [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. ]

Measure Type	Secondary
Measure Name	Median Duration of Response (DoR) by ICR and Investigator Assessment Using RECIST 1.1
Measure Description	DoR was defined as the time from date of first documented response (which was subsequently confirmed) until date of documented progression or death in the absence of disease progression (i.e. date of progression free survival [PFS] event or censoring – date of first response + 1). The end of response coincided with the date of progression or death from any cause used for the PFS endpoint. The time of initial response was defined as the latest of the dates used towards the first visit that was CR or PR that was subsequently confirmed. If a patient did not progress following a response, the PFS censoring time was used. The Investigator assessment was based on the FAS and the ICR used the EFR analysis set. The median DoR for each assessment is presented and was calculated using the Kaplan-Meier technique.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The EFR set included all patients who received at least 1 dose of IP and had measurable disease at baseline according to the independent review of baseline imaging data. The FAS included all patients who received at least 1 dose of either of the IPs.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	60
Median Duration of Response (DoR) by ICR and Investigator Assessment Using RECIST 1.1 [units: weeks] Median (95% Confidence Interval)
ICR assessment (EFR analysis set)	36.0 (24.4 to 45.0)
Investigator assessment (FAS)	45.0 (25.0 to 58.0)

No statistical analysis provided for Median Duration of Response (DoR) by ICR and Investigator Assessment Using RECIST 1.1

4. Secondary Outcome Measure: Disease Control Rate (DCR) by ICR and Investigator Assessment Using RECIST 1.1 [ Time Frame: From baseline up to 6 months after first doses of IPs. RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. ]

Measure Type	Secondary
Measure Name	Disease Control Rate (DCR) by ICR and Investigator Assessment Using RECIST 1.1
Measure Description	The DCR was defined as the percentage of patients who had a best overall response of CR, PR or Stable Disease (SD) at 6 months. CR: Disappearance of all TLs and NTLs since baseline; any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of TL, referencing the baseline sum of diameters. SD: Neither sufficient shrinkage of TLs to qualify for PR nor sufficient increase to qualify for progressive disease (PD) (at least a 20% increase in the sum of diameters of TLs with an absolute increase of at least 5 mm and progression of existing NTLs). Patients had to have demonstrated SD for at least 23 weeks following the start of treatment. The Investigator assessment was based on the FAS and the ICR used the EFR analysis set. The percentage of patients with disease control for each assessment is presented.
Time Frame	From baseline up to 6 months after first doses of IPs. RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The EFR set included all patients who received at least 1 dose of IP and had measurable disease at baseline according to the independent review of baseline imaging data. The FAS included all patients who received at least 1 dose of either of the IPs.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	60
Disease Control Rate (DCR) by ICR and Investigator Assessment Using RECIST 1.1 [units: percentage of patients] Number (95% Confidence Interval)
ICR assessment (EFR analysis set)	23.7 (13.6 to 36.6)
Investigator assessment (FAS)	26.7 (16.1 to 39.7)

No statistical analysis provided for Disease Control Rate (DCR) by ICR and Investigator Assessment Using RECIST 1.1

5. Secondary Outcome Measure: Median PFS by ICR and Investigator Assessment Using RECIST 1.1 [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression. ]

Measure Type	Secondary
Measure Name	Median PFS by ICR and Investigator Assessment Using RECIST 1.1
Measure Description	PFS was defined as the time from date of first dose of IP until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from treatment or received another anti-cancer therapy prior to progression (i.e. date of PFS event or censoring – date of first dose + 1). Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The median PFS, calculated using the Kaplan-Meier technique, is presented for the ICR and the Investigator assessment, both based on the FAS.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). RECIST assessments were performed at baseline and every 8 weeks (+/- 1 week) after first doses of IPs until disease progression.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all patients who received at least 1 dose of either of the IPs.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	60
Median PFS by ICR and Investigator Assessment Using RECIST 1.1 [units: months] Median (95% Confidence Interval)
ICR assessment (FAS)	5.1 (3.5 to 5.5)
Investigator assessment (FAS)	3.8 (3.5 to 6.4)

No statistical analysis provided for Median PFS by ICR and Investigator Assessment Using RECIST 1.1

6. Secondary Outcome Measure: Median Time to Treatment Discontinuation or Death (TDT) [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). ]

Measure Type	Secondary
Measure Name	Median Time to Treatment Discontinuation or Death (TDT)
Measure Description	The median time to discontinuation of IPs or death was defined as the time from the date of first dose of IP to the earlier of the date of discontinuation of both IPs, or death date. If 1 IP was discontinued before the other, the TDT reflected the time from the date of first dose to the earliest IP discontinuation date. The median TDT was calculated using the Kaplan-Meier technique.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all patients who received at least 1 dose of either of the IPs.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	60
Median Time to Treatment Discontinuation or Death (TDT) [units: months] Median (95% Confidence Interval)	3.5 (2.7 to 5.1)

No statistical analysis provided for Median Time to Treatment Discontinuation or Death (TDT)

7. Secondary Outcome Measure: Median Overall Survival (OS) [ Time Frame: From baseline until death due to any cause, assessed until primary analysis DCO (8 months after last patient received their first dose of IPs). ]

Measure Type	Secondary
Measure Name	Median Overall Survival (OS)
Measure Description	OS was defined as the time from the date of first dose of IP until death due to any cause regardless of whether the patient withdrew from treatment or received another anti-cancer therapy (i.e. date of death or censoring – date of first dose + 1). Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. The median OS was calculated using the Kaplan-Meier technique.
Time Frame	From baseline until death due to any cause, assessed until primary analysis DCO (8 months after last patient received their first dose of IPs).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all patients who received at least 1 dose of either of the IPs.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	60
Median Overall Survival (OS) [units: months] Median (95% Confidence Interval)	13.2 (9.4 to 16.4)

No statistical analysis provided for Median Overall Survival (OS)

8. Secondary Outcome Measure: Best Observed Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 scales [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). EORTC QLQ-C30 assessments were performed at baseline and every 8 weeks relative to first dose until discontinuation of IPs. ]

Measure Type	Secondary
Measure Name	Best Observed Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 scales
Measure Description	The EORTC QLQ-C30 questionnaire assesses health-related quality of life (HRQoL). The questions are grouped into a global health status/QoL scale, 5 functional scales (physical, role, emotional, cognitive and social), 3 multi-item symptom scales (fatigue, pain, nausea/ vomiting), 5 single items assessing cancer symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhea), and 1 item on the financial impact of the disease. Each scale/item is scored from 0 to 100. Higher scores on the global health status/QoL scale and functional scales indicate better health status/function. Higher scores on the symptom scales/items indicate a greater symptom burden. A 10-point change in the score was used to identify patients who improved, stayed the same or deteriorated from baseline. The number of patients with a best observed change from baseline response of improved, stayed the same or deteriorated for each EORTC QLQ-C30 scale/item is presented.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). EORTC QLQ-C30 assessments were performed at baseline and every 8 weeks relative to first dose until discontinuation of IPs.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all patients who received at least 1 dose of either of the IPs. Only patients with non-missing baseline and post-baseline data were included in the analysis.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	36
Best Observed Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 scales [units: Participants]
Appetite loss: improved	0
Appetite loss: stayed the same	22
Appetite loss: deteriorated	14
Cognitive functioning: improved	2
Cognitive functioning: stayed the same	23
Cognitive functioning: deteriorated	11
Constipation: improved	2
Constipation: stayed the same	27
Constipation: deteriorated	7
Diarrhea: improved	0
Diarrhea: stayed the same	22
Diarrhea: deteriorated	14
Dyspnea: improved	2
Dyspnea: stayed the same	24
Dyspnea: deteriorated	10
Emotional functioning: improved	2
Emotional functioning: stayed the same	31
Emotional functioning: deteriorated	3
Fatigue: improved	4
Fatigue: stayed the same	11
Fatigue: deteriorated	21
Financial difficulties: improved	2
Financial difficulties: stayed the same	32
Financial difficulties: deteriorated	2
Global Health Status / QoL: improved	1
Global Health Status / QoL: stayed the same	19
Global Health Status / QoL: deteriorated	16
Insomnia: improved	3
Insomnia: stayed the same	26
Insomnia: deteriorated	7
Nausea / vomiting: improved	4
Nausea / vomiting: stayed the same	19
Nausea / vomiting: deteriorated	13
Pain: improved	9
Pain: stayed the same	21
Pain: deteriorated	6
Physical functioning: improved	0
Physical functioning: stayed the same	24
Physical functioning: deteriorated	12
Role functioning: improved	1
Role functioning: stayed the same	18
Role functioning: deteriorated	17
Social functioning: improved	1
Social functioning: stayed the same	22
Social functioning: deteriorated	13

No statistical analysis provided for Best Observed Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 scales

9. Secondary Outcome Measure: Best Observed Change from Baseline in EORTC QLQ-OV28 [ Time Frame: From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). EORTC QLQ-OV28 assessments were performed at baseline and every 8 weeks relative to first dose until discontinuation of IPs. ]

Measure Type	Secondary
Measure Name	Best Observed Change from Baseline in EORTC QLQ-OV28
Measure Description	The EORTC QLQ-OV28 is specific for ovarian cancer and consists of 28 items assessing abdominal/gastrointestinal symptoms (6 items), peripheral neuropathy (2 items), other chemotherapy side effects (5 items), hormonal symptoms (2 items), body image (2 items), attitudes to disease/treatment (3 items), sexuality (4 items) and 4 other single items. Each scale was scored from 0 to 100 with higher scores on the symptom scales indicating greater symptom burden. The best observed change from baseline is presented for each EORTC QLQ-OV28 scale, where a 10-point change in the score was used to identify patients who improved, stayed the same or deteriorated. The number of patients with a best observed change from baseline response of improved, stayed the same, or deteriorated in the EORTC QLQ-OV28 is presented.
Time Frame	From baseline to primary analysis DCO (8 months after last patient received their first dose of IPs). EORTC QLQ-OV28 assessments were performed at baseline and every 8 weeks relative to first dose until discontinuation of IPs.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The FAS included all patients who received at least 1 dose of either of the IPs. Only patients with non-missing baseline and post-baseline data were included in the analysis.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Measured Values

	Cediranib + Olaparib
Number of Participants Analyzed [units:participants]	32
Best Observed Change from Baseline in EORTC QLQ-OV28 [units: Participants]
Abdominal / Gastrointestinal: improved	2
Abdominal / Gastrointestinal: stayed the same	18
Abdominal / Gastrointestinal: deteriorated	12
Attitude to disease / treatment: improved	3
Attitude to disease / treatment: stayed the same	16
Attitude to disease / treatment: deteriorated	13
Body image: improved	7
Body image: stayed the same	19
Body image: deteriorated	6
Chemotherapy side effects: improved	1
Chemotherapy side effects: stayed the same	24
Chemotherapy side effects: deteriorated	7
Hormonal: improved	2
Hormonal: stayed the same	25
Hormonal: deteriorated	5
Other single items: improved	1
Other single items: stayed the same	19
Other single items: deteriorated	12
Peripheral neuropathy: improved	1
Peripheral neuropathy: stayed the same	24
Peripheral neuropathy: deteriorated	7
Sexuality: improved	2
Sexuality: stayed the same	26
Sexuality: deteriorated	4

No statistical analysis provided for Best Observed Change from Baseline in EORTC QLQ-OV28

Serious Adverse Events

Time Frame	Adverse events were collected with an onset date on or after the date of first dose of IP and up to and including 30 days following the date of last dose of IP. Assessed until primary analysis DCO (over a period of approximately 2 years and 7 months).
Additional Description	The safety analysis set included all patients who received at least 1 dose of either IP.

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Serious Adverse Events

Cediranib + Olaparib

Total, serious adverse events

# participants affected / at risk

22/60 (36.67%)

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Cardiac disorders

Coronary artery disease¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Endocrine disorders

Hyperparathyroidism¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Ascites¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Enterocutaneous fistula¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Intestinal obstruction¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Large intestinal obstruction¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

4/60 (6.67%)

# events

Gastrointestinal disorders

Small intestinal obstruction¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

2/60 (3.33%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Hepatobiliary disorders

Drug-induced liver injury¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Hepatobiliary disorders

Hepatic encephalopathy¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Infections and infestations

Sepsis¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Injury, poisoning and procedural complications

Femur fracture¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Investigations

Blood pressure increased¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Metabolism and nutrition disorders

Hypovolaemia¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Nervous system disorders

Ataxia¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Nervous system disorders

Posterior reversible encephalopathy syndrome¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Nervous system disorders

Seizure¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Renal and urinary disorders

Acute kidney injury¹,^†

# participants affected / at risk

2/60 (3.33%)

# events

Respiratory, thoracic and mediastinal disorders

Hypoxia¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Respiratory, thoracic and mediastinal disorders

Pleural effusion¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

1/60 (1.67%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 22.0

Other Adverse Events

Time Frame	Adverse events were collected with an onset date on or after the date of first dose of IP and up to and including 30 days following the date of last dose of IP. Assessed until primary analysis DCO (over a period of approximately 2 years and 7 months).
Additional Description	The safety analysis set included all patients who received at least 1 dose of either IP.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Cediranib + Olaparib	Patients received a combination of cediranib 30 mg orally qd and olaparib 200 mg orally bid until objective radiological disease progression, unacceptable toxicity or withdrawal of consent. Dose modification was allowed per protocol-defined guidelines.

Other Adverse Events

Cediranib + Olaparib

Total, other (not including serious) adverse events

# participants affected / at risk

56/60 (93.33%)

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

12/60 (20.00%)

# events

Blood and lymphatic system disorders

Thrombocytopenia¹,^†

# participants affected / at risk

6/60 (10.00%)

# events

Endocrine disorders

Hypothyroidism¹,^†

# participants affected / at risk

9/60 (15.00%)

# events

Gastrointestinal disorders

Abdominal distension¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

20/60 (33.33%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

17/60 (28.33%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

40/60 (66.67%)

# events

Gastrointestinal disorders

Dry mouth¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Gastrointestinal disorders

Gastrooesophageal reflux disease¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

39/60 (65.00%)

# events

Gastrointestinal disorders

Oral pain¹,^†

# participants affected / at risk

6/60 (10.00%)

# events

Gastrointestinal disorders

Stomatitis¹,^†

# participants affected / at risk

6/60 (10.00%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

23/60 (38.33%)

# events

General disorders and administration site conditions

Asthenia¹,^†

# participants affected / at risk

6/60 (10.00%)

# events

General disorders and administration site conditions

Fatigue¹,^†

# participants affected / at risk

41/60 (68.33%)

# events

General disorders and administration site conditions

Mucosal inflammation¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

9/60 (15.00%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

10/60 (16.67%)

# events

Investigations

Aspartate aminotransferase increased¹,^†

# participants affected / at risk

6/60 (10.00%)

# events

Investigations

Blood alkaline phosphatase increased¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Investigations

Blood creatinine increased¹,^†

# participants affected / at risk

9/60 (15.00%)

# events

Investigations

Blood thyroid stimulating hormone increased¹,^†

# participants affected / at risk

7/60 (11.67%)

# events

Investigations

Platelet count decreased¹,^†

# participants affected / at risk

7/60 (11.67%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

8/60 (13.33%)

# events

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

21/60 (35.00%)

# events

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

10/60 (16.67%)

# events

Metabolism and nutrition disorders

Hypoalbuminaemia¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Metabolism and nutrition disorders

Hypokalaemia¹,^†

# participants affected / at risk

10/60 (16.67%)

# events

Metabolism and nutrition disorders

Hypomagnesaemia¹,^†

# participants affected / at risk

15/60 (25.00%)

# events

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

12/60 (20.00%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

6/60 (10.00%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

4/60 (6.67%)

# events

Musculoskeletal and connective tissue disorders

Muscle spasms¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Musculoskeletal and connective tissue disorders

Muscular weakness¹,^†

# participants affected / at risk

4/60 (6.67%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal pain¹,^†

# participants affected / at risk

4/60 (6.67%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

7/60 (11.67%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

7/60 (11.67%)

# events

Nervous system disorders

Dysgeusia¹,^†

# participants affected / at risk

11/60 (18.33%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

21/60 (35.00%)

# events

Nervous system disorders

Neuropathy peripheral¹,^†

# participants affected / at risk

7/60 (11.67%)

# events

Psychiatric disorders

Anxiety¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Psychiatric disorders

Insomnia¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Renal and urinary disorders

Proteinuria¹,^†

# participants affected / at risk

7/60 (11.67%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

10/60 (16.67%)

# events

Respiratory, thoracic and mediastinal disorders

Dysphonia¹,^†

# participants affected / at risk

10/60 (16.67%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

14/60 (23.33%)

# events

Skin and subcutaneous tissue disorders

Rash¹,^†

# participants affected / at risk

5/60 (8.33%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

39/60 (65.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 22.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Institution and the PI are entitled to publish the results of or make presentations related to the study, provided that any publication or presentation to be made within 2 years of study completion require the Company’s prior written consent. All publications or presentations shall be consistent with academic standards and International Committee of Medical Journal Editors guidelines, not be false or misleading, comply with all Applicable Laws and not be made for any commercial purpose.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

CSR synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

Tsveta Milenkova

Tsveta.Milenkova@astrazeneca.com

Investigators

Principal Investigator

Jung-Min Lee

NIH - National Cancer Institute

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSR synopsis

Trial Results Summaries